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1
Melnikov, Dmitriy V., Zachery K. Hulings, and Maria E. Gracheva. "Concentration Polarization, Surface Charge, and Ionic Current Blockade in Nanopores." Journal of Physical Chemistry C 124, no. 36 (August 11, 2020): 19802–8. http://dx.doi.org/10.1021/acs.jpcc.0c04829.
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Tsutsui, Makusu, Kazumichi Yokota, Akihide Arima, Wataru Tonomura, Masateru Taniguchi, Takashi Washio, and Tomoji Kawai. "Temporal Response of Ionic Current Blockade in Solid-State Nanopores." ACS Applied Materials & Interfaces 10, no. 40 (September 11, 2018): 34751–57. http://dx.doi.org/10.1021/acsami.8b11819.
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Tsutsui, Makusu, Yuhui He, Kazumichi Yokota, Akihide Arima, Sadato Hongo, Masateru Taniguchi, Takashi Washio, and Tomoji Kawai. "Particle Trajectory-Dependent Ionic Current Blockade in Low-Aspect-Ratio Pores." ACS Nano 10, no. 1 (December 7, 2015): 803–9. http://dx.doi.org/10.1021/acsnano.5b05906.
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Tsutsui, Makusu, Kazumichi Yokota, Tomoko Nakada, Akihide Arima, Wataru Tonomura, Masateru Taniguchi, Takashi Washio, and Tomoji Kawai. "Silicon substrate effects on ionic current blockade in solid-state nanopores." Nanoscale 11, no. 10 (2019): 4190–97. http://dx.doi.org/10.1039/c8nr09042d.
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Diaz Carral, Angel, Chandra Shekar Sarap, Ke Liu, Aleksandra Radenovic, and Maria Fyta. "2D MoS 2 nanopores: ionic current blockade height for clustering DNA events." 2D Materials 6, no. 4 (July 8, 2019): 045011. http://dx.doi.org/10.1088/2053-1583/ab2c38.
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Song, S. C., J. A. Beatty, and C. J. Wilson. "The ionic mechanism of membrane potential oscillations and membrane resonance in striatal LTS interneurons." Journal of Neurophysiology 116, no. 4 (October 1, 2016): 1752–64. http://dx.doi.org/10.1152/jn.00511.2016.
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Striatal low-threshold spiking (LTS) interneurons spontaneously transition to a depolarized, oscillating state similar to that seen after sodium channels are blocked. In the depolarized state, whether spontaneous or induced by sodium channel blockade, the neurons express a 3- to 7-Hz oscillation and membrane impedance resonance in the same frequency range. The membrane potential oscillation and membrane resonance are expressed in the same voltage range (greater than −40 mV). We identified and recorded from LTS interneurons in striatal slices from a mouse that expressed green fluorescent protein under the control of the neuropeptide Y promoter. The membrane potential oscillation depended on voltage-gated calcium channels. Antagonism of L-type calcium currents (CaV1) reduced the amplitude of the oscillation, whereas blockade of N-type calcium currents (CaV2.2) reduced the frequency. Both calcium sources activate a calcium-activated chloride current (CaCC), the blockade of which abolished the oscillation. The blocking of any of these three channels abolished the membrane resonance. Immunohistochemical staining indicated anoctamin 2 (ANO2), and not ANO1, as the CaCC source. Biophysical modeling showed that CaV1, CaV2.2, and ANO2 are sufficient to generate a membrane potential oscillation and membrane resonance, similar to that in LTS interneurons. LTS interneurons exhibit a membrane potential oscillation and membrane resonance that are both generated by CaV1 and CaV2.2 activating ANO2. They can spontaneously enter a state in which the membrane potential oscillation dominates the physiological properties of the neuron.
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Vogalis, F., R. J. Lang, R. A. Bywater, and G. S. Taylor. "Voltage-gated ionic currents in smooth muscle cells of guinea pig proximal colon." American Journal of Physiology-Cell Physiology 264, no. 3 (March 1, 1993): C527—C536. http://dx.doi.org/10.1152/ajpcell.1993.264.3.c527.
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Smooth muscle cells enzymatically dispersed from the circular muscle layer of the guinea pig colon were examined for the expression of voltage-gated ionic currents using the whole cell patch-clamp technique. Three outward currents and one inward current were identified and characterized. The inward current, at physiological potentials, was generated by a voltage-gated Ca2+ conductance that was permeable to Ba2+ but blocked by Cd2+ (0.1 mM) or nifedipine (10 microM). The three outward currents were carried by K+, abolished when cells were internally perfused with Cs+, and distinguished by their sensitivity to known K(+)-channel blockers. A K+ current dependent on Ca2+ entry was activated at potentials positive to -40 mV and abolished by low concentrations (2-5 mM) of tetraethylammonium (TEA). A delayed rectifier-type K+ current activated slowly at potentials positive to -30 mV, showed little inactivation, and was abolished by higher concentrations (> 5 mM) of TEA. A rapidly activating and inactivating transient outward K+ current (IKto), activated at potentials positive to -60 mV, was abolished by low concentrations (3-5 mM) of 4-aminopyridine and was relatively insensitive to TEA (10-126 mM) blockade. The overlapping steady-state activation and inactivation curves of IKto revealed a "window current" phenomenon between -60 and -40 mV. The rapid activation of IKto at membrane potentials more negative than those for Ca2+ current suggests that IKto will influence cell excitability by delaying the upstroke of the action potential. The present data provide an ionic basis for the regenerative excitatory activity in the circular muscle layer of the guinea pig proximal colon.
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Wasserstrom, J. A., and J. J. Salata. "Basis for tetrodotoxin and lidocaine effects on action potentials in dog ventricular myocytes." American Journal of Physiology-Heart and Circulatory Physiology 254, no. 6 (June 1, 1988): H1157—H1166. http://dx.doi.org/10.1152/ajpheart.1988.254.6.h1157.
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We studied the effects of tetrodotoxin (TTX) and lidocaine on transmembrane action potentials and ionic currents in dog isolated ventricular myocytes. TTX (0.1-1 x 10(-5) M) and lidocaine (0.5-2 x 10(-5) M) decreased action potential duration, but only TTX decreased the maximum rate of depolarization (Vmax). Both TTX (1-2 x 10(-5) M) and lidocaine (2-5 x 10(-5) M) blocked a slowly inactivating toward current in the plateau voltage range. The voltage- and time-dependent characteristics of this current are virtually identical to those described in Purkinje fibers for the slowly inactivating inward Na+ current. In addition, TTX abolished the outward shift in net current at plateau potentials caused by lidocaine alone. Lidocaine had no detectable effect on the slow inward Ca2+ current and the inward K+ current rectifier, Ia. Our results indicate that 1) there is a slowly inactivating inward Na+ current in ventricular cells similar in time, voltage, and TTX sensitivity to that described in Purkinje fibers; 2) both TTX and lidocaine shorten ventricular action potentials by reducing this slowly inactivating Na+ current; 3) lidocaine has no additional actions on other ionic currents that contribute to its ability to abbreviate ventricular action potentials; and 4) although both agents shorten the action potential by the same mechanism, only TTX reduces Vmax. This last point suggests that TTX produces tonic block of Na+ current, whereas lidocaine may produce state-dependent Na+ channel block, namely, blockade of Na+ current only after Na+ channels have already been opened (inactivated-state block).
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Nishimura, Yoshihiro, Masaru Asahi, Koichi Saitoh, Hirofumi Kitagawa, Yuichi Kumazawa, Kunio Itoh, Min Lin, et al. "Ionic Mechanisms Underlying Burst Firing of Layer III Sensorimotor Cortical Neurons of the Cat: An In Vitro Slice Study." Journal of Neurophysiology 86, no. 2 (August 1, 2001): 771–81. http://dx.doi.org/10.1152/jn.2001.86.2.771.
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We examined the ionic mechanisms underlying burst firing in layer III neurons from cat sensorimotor cortex by intracellular recording in a brain slice. Regular spiking was observed in 77.4% of 137 neurons in response to constant intracellular current pulses of 0.5- to 1-s duration. The rest of the neurons showed burst firing. An initial burst followed by regular-spike firing was seen in 71.0% of 31 bursting neurons. The rest of the bursting neurons ( n = 9) exhibited repetitive bursting. In the bursting neurons, spikes comprising the burst were triggered from the afterdepolarization (ADP) of the first spike of the burst. We examined the ionic mechanisms underlying the ADP by applying channel-blocking agents. The ADP was enhanced (rather than blocked) by Ca2+ channel blockade. This enhancement of the ADP by Ca2+channel blockade was apparent even after blockade of the afterhyperpolarization by apamin or intracellular Ca2+ chelation by EGTA. The firing rate of the regular-spiking cells was increased by apamin, intracellular EGTA or Ca2+ channel blockers. In 17.9% of the neurons examined ( n = 56), these agents switched the regular-spiking pattern into a bursting one. Burst firing could not be changed to regular spiking by these agents. Four neurons that responded with a single initial burst in control solution responded with repetitive bursting after application of these agents. We conclude that the main function of Ca2+ influx in layer III neurons is to activate Ca2+-dependent K+ conductance, which prevents or limits burst firing. At a time when spike amplitude was unchanged, the ADP was blocked and the burst firing changed to regular spiking by extracellularly applied tetrodotoxin (TTX) or intracellularly applied N-(2,6-dimethylphenylcarbamoylmethyl) triethyl ammonium bromide (QX314). We concluded that a TTX- and QX314-sensitive Na+ current underlies the ADP and therefore contributes to the burst firing of layer III neurons from the cat cortex.
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Bhattacharya, Swati, Jejoong Yoo, and Aleksei Aksimentiev. "Water Mediates Recognition of DNA Sequence via Ionic Current Blockade in a Biological Nanopore." ACS Nano 10, no. 4 (April 15, 2016): 4644–51. http://dx.doi.org/10.1021/acsnano.6b00940.
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Glasgow, Stephen D., and C. Andrew Chapman. "Conductances Mediating Intrinsic Theta-Frequency Membrane Potential Oscillations in Layer II Parasubicular Neurons." Journal of Neurophysiology 100, no. 5 (November 2008): 2746–56. http://dx.doi.org/10.1152/jn.90351.2008.
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Ionic conductances that generate membrane potential oscillations in neurons of layer II of the parasubiculum were studied using whole cell current-clamp recordings in horizontal slices from the rat brain. Blockade of ionotropic glutamate and GABA synaptic transmission did not reduce the power of the oscillations, indicating that oscillations are not dependent on synaptic inputs. Oscillations were eliminated when cells were hyperpolarized 6–10 mV below spike threshold, indicating that they are mediated by voltage-dependent conductances. Application of TTX completely eliminated oscillations, suggesting that Na+ currents are required for the generation of the oscillations. Oscillations were not reduced by blocking Ca2+ currents with Cd2+ or Ca2+-free artificial cerebrospinal fluid, or by blocking K+ conductances with either 50 μM or 5 mM 4-aminopyridine (4-AP), 30 mM tetraethylammonium (TEA), or Ba2+(1–2 mM). Oscillations also persisted during blockade of the muscarinic-dependent K+ current, IM, using the selective antagonist XE-991 (10 μM). However, oscillations were significantly attenuated by blocking the hyperpolarization-activated cationic current Ih with Cs+ and were almost completely blocked by the more potent Ih blocker ZD7288 (100 μM). Intrinsic membrane potential oscillations in neurons of layer II of the parasubiculum are therefore likely driven by an interaction between an inward persistent Na+ current and time-dependent deactivation of Ih. These voltage-dependent conductances provide a mechanism for the generation of membrane potential oscillations that can help support rhythmic network activity within the parasubiculum during theta-related behaviors.
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Courtemanche, Marc, Rafael J. Ramirez, and Stanley Nattel. "Ionic mechanisms underlying human atrial action potential properties: insights from a mathematical model." American Journal of Physiology-Heart and Circulatory Physiology 275, no. 1 (July 1, 1998): H301—H321. http://dx.doi.org/10.1152/ajpheart.1998.275.1.h301.
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The mechanisms underlying many important properties of the human atrial action potential (AP) are poorly understood. Using specific formulations of the K+, Na+, and Ca2+ currents based on data recorded from human atrial myocytes, along with representations of pump, exchange, and background currents, we developed a mathematical model of the AP. The model AP resembles APs recorded from human atrial samples and responds to rate changes, L-type Ca2+ current blockade, Na+/Ca2+ exchanger inhibition, and variations in transient outward current amplitude in a fashion similar to experimental recordings. Rate-dependent adaptation of AP duration, an important determinant of susceptibility to atrial fibrillation, was attributable to incomplete L-type Ca2+ current recovery from inactivation and incomplete delayed rectifier current deactivation at rapid rates. Experimental observations of variable AP morphology could be accounted for by changes in transient outward current density, as suggested experimentally. We conclude that this mathematical model of the human atrial AP reproduces a variety of observed AP behaviors and provides insights into the mechanisms of clinically important AP properties.
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Wolff, Matthias, Andrea Olschewski, Werner Vogel, and Gunter Hempelmann. "Meperidine Suppresses the Excitability of Spinal Dorsal Horn Neurons." Anesthesiology 100, no. 4 (April 1, 2004): 947–55. http://dx.doi.org/10.1097/00000542-200404000-00027.
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Background In addition to local anesthetics, meperidine has been successfully used for local anesthesia. When applied intrathecally, the dorsal horn neurons of the superficial laminae are exposed to high concentrations of meperidine. These cells represent an important point for the transmission of pain information. This study investigated the blocking effects of meperidine on different ionic currents of spinal dorsal horn neurons and, in particular, its impact on the generation of action potentials. Methods Using a combination of the patch clamp technique and the entire soma isolation method, the action of meperidine on voltage-gated Na+ and K+ currents in spinal dorsal horn neurons of rats was described. Current clamp recordings from intact neurons showed the functional relevance of the ion current blockade for the generation of action potentials. Results Externally applied meperidine reversibly blocked voltage-gated Na+ currents with a half-maximum inhibiting concentration (IC50) of 112 microM. During repetitive stimulation, a slight phasic block occurred. In addition, A-type K+ currents and delayed-rectifier K+ currents were affected in a dose-dependent manner, with IC50 values of 102 and 52 microM, respectively. In the current clamp mode, single action potentials were suppressed by meperidine. The firing frequency was lowered to 54% at concentrations (100 microM) insufficient for the suppression of a single action potential. Conclusions Meperidine inhibits the complex mechanism of generating action potentials in spinal dorsal horn neurons by the blockade of voltage-gated Na+ and K+ channels. This can contribute to the local anesthetic effect of meperidine during spinal anesthesia.
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Sun, Li-Zhen, and Meng-Bo Luo. "Study on the polymer translocation induced blockade ionic current inside a nanopore by Langevin dynamics simulation." Journal of Physics: Condensed Matter 25, no. 46 (October 7, 2013): 465101. http://dx.doi.org/10.1088/0953-8984/25/46/465101.
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Moretti, Manola, Enzo Di Fabrizio, Stefano Cabrini, Rita Musetti, Francesco De Angelis, and Giuseppe Firrao. "An ON/OFF biosensor based on blockade of ionic current passing through a solid-state nanopore." Biosensors and Bioelectronics 24, no. 1 (September 2008): 141–47. http://dx.doi.org/10.1016/j.bios.2008.03.047.
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Jassar, Balvinder S., Kim H. Harris, Paula M. Ostashewski, and Jack H. Jhamandas. "Ionic Mechanisms of Action of Neurotensin in Acutely Dissociated Neurons From the Diagonal Band of Broca of the Rat." Journal of Neurophysiology 81, no. 1 (January 1, 1999): 234–46. http://dx.doi.org/10.1152/jn.1999.81.1.234.
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Jassar, Balvinder S., Kim H. Harris, Paula M. Ostashewski, and Jack H. Jhamandas. Ionic mechanisms of action of neurotensin in acutely dissociated neurons from the diagonal band of Broca of the rat. J. Neurophysiol. 81: 234–246, 1999. Whole cell recordings were performed on acutely dissociated neurons from the horizontal limb of the diagonal band of Broca (hDBB) from rats to elucidate the ionic mechanisms of action of neurotensin. Neurotensin caused a decrease in whole cell voltage-activated outward currents and failed to elicit a response when Ca2+ influx was blocked by changing the external solution to the one containing 0 mM Ca2+ and 50 μM Cd2+, suggesting the involvement of Ca2+-dependent conductances. Charybdotoxin, a specific blocker of voltage-sensitive calcium-activated K+ channels ( I C), caused a decrease in outward currents comparable with that caused by blocking calcium influx and occluded the neurotensin-induced decrease in outward currents. Similarly, 50 μM tetraethylammonium ions also blocked the neurotensin response. Also neurotensin reduced whole cell barium currents ( I Ba) and calcium currents ( I Ca). Amiloride and ω-conotoxin GVIA, but not nimodipine, were able to eliminate the neurotensin-induced decrease in I Ba. Thus T- and N- but not L-type calcium channels are subject to modulation by neurotensin, and this may account for its effects on I C. The predicted changes in action potential as a result of the blockade of currents through calcium channels culminating into changes in I C were confirmed in the bridge current-clamp recordings. Specifically, neurotensin application led to depolarization of the resting membrane potential, broadening of spike and a decrease in afterhyperpolarization and accommodation. These alterations in action potential characteristics that resulted in increased firing rate and excitability of the hDBB neurons also were produced by application of charybdotoxin. Neurotensin effects on these properties were occluded by 2 - [(1 – 7 - chloro - 4 - quinolinyl) - 5 - (2, 6 - di - methoxyphenyl) pyrazol-3-yl) carbonylamino] tricyclo (3.3.1.1.)decan-2-carboxylic acid, a nonpeptide high-affinity neurotensin receptor antagonist. Neurotensin blockade of I C, possibly through I Ca, is a potential physiological mechanism whereby this peptide may evoke alterations in the cortical arousal, sleep-wake cycle, and theta rhythm.
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ANDERSON, PETER A. V., and M. CRAIG MCKAY. "The Electrophysiology of Cnidocytes." Journal of Experimental Biology 133, no. 1 (November 1, 1987): 215–30. http://dx.doi.org/10.1242/jeb.133.1.215.
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Electrical properties of cnidocytes isolated from the hydroid Cladonema and the scyphomedusa Chrysaora were examined using current- and voltage-clamp recording techniques. The stenoteles of Cladonema produced action potentials when depolarized above 0 m V. The inward current that produced the action potential was a Na+ current. These cells also possessed an A-current and a K-current. Atrichous isorhizas from Chrysaora did not spike and did not have any inward currents. All cells examined had K-currents, some had A-currents also. Very few cnidocytes discharged during the course of the recordings, irrespective of the degree to which they were depolarized or hyperpolarized, or the presence or selective blockade of any ionic currents. When discharge did occur it could never be correlated with any obvious electrophysiological event. Recordings from cnidocytes in situ in tentacles of the siphonophore Physalia indicate that these cells do not spike. Their current/voltage relationships were linear. They too did not discharge in response to changes in membrane potential, suggesting that the failure of isolated cnidocytes to discharge cannot be attributed to the isolation procedure.
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Sciamanna, Giuseppe, and Charles J. Wilson. "The ionic mechanism of gamma resonance in rat striatal fast-spiking neurons." Journal of Neurophysiology 106, no. 6 (December 2011): 2936–49. http://dx.doi.org/10.1152/jn.00280.2011.
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Striatal fast-spiking (FS) cells in slices fire in the gamma frequency range and in vivo are often phase-locked to gamma oscillations in the field potential. We studied the firing patterns of these cells in slices from rats ages 16–23 days to determine the mechanism of their gamma resonance. The resonance of striatal FS cells was manifested as a minimum frequency for repetitive firing. At rheobase, cells fired a doublet of action potentials or doublets separated by pauses, with an instantaneous firing rate averaging 44 spikes/s. The minimum rate for sustained firing was also responsible for the stuttering firing pattern. Firing rate adapted during each episode of firing, and bursts were terminated when firing was reduced to the minimum sustainable rate. Resonance and stuttering continued after blockade of Kv3 current using tetraethylammonium (0.1–1 mM). Both gamma resonance and stuttering were strongly dependent on Kv1 current. Blockade of Kv1 channels with dendrotoxin-I (100 nM) completely abolished the stuttering firing pattern, greatly lowered the minimum firing rate, abolished gamma-band subthreshold oscillations, and slowed spike frequency adaptation. The loss of resonance could be accounted for by a reduction in potassium current near spike threshold and the emergence of a fixed spike threshold. Inactivation of the Kv1 channel combined with the minimum firing rate could account for the stuttering firing pattern. The resonant properties conferred by this channel were shown to be adequate to account for their phase-locking to gamma-frequency inputs as seen in vivo.
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Nathan, R. D., K. Kanai, R. B. Clark, and W. Giles. "Selective block of calcium current by lanthanum in single bullfrog atrial cells." Journal of General Physiology 91, no. 4 (April 1, 1988): 549–72. http://dx.doi.org/10.1085/jgp.91.4.549.
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A single suction microelectrode voltage-clamp technique was used to study the actions of lanthanum ions (La3+) on ionic currents in single cells isolated from bullfrog right atrium. La3+, added as LaCl3, blocked the "slow" inward Ca2+ current (ICa) in a dose-dependent fashion; 10(-5) M produced complete inhibition. This effect was best fitted by a dose-response curve that was calculated assuming 1:1 binding of La3+ to a site having a dissociation constant of 7.5 x 10(-7) M. La3+ block was reversed (to 90% of control ICa) following washout and, in the presence of 10(-5) M La3+, was antagonized by raising the Ca2+ concentration from 2.5 to 7.5 mM (ICa recovered to 56% of the control). However, the latter effect took approximately 1 h to develop. Concentrations of La3+ that reduced ICa by 12-67%, 0.1-1.5 x 10(-6) M, had no measurable effect upon the voltage dependence of steady state ICa inactivation, which suggest that at these concentrations there are no significant surface-charge effects of La3+ on this gating mechanism. Three additional findings indicate that doses of La3+ that blocked ICa failed to produce nonspecific effects: (a) 10(-5) M La3+ had no measurable effect on the time-independent inwardly rectifying current, IK1; (b) the same concentration had no effect on the kinetics, amplitude, or voltage dependence of a time- and voltage-dependent K+ current, IK; and (c) 10(-4) M La3+ did not alter the size of the tetrodotoxin-sensitive inward Na+ current, INa, or the voltage dependence of its steady state inactivation. Higher concentrations (0.5-1.0 mM) reduced both IK1 and IK, and shifted the steady state activation curve for IK toward more positive potentials, presumably by reducing the external surface potential. Our results suggest that at a concentration of less than or equal to 10(-5) M, La3+ inhibits ICa selectively by direct blockade of Ca channels rather than by altering the external surface potential. At higher concentrations, La3+ exhibits nonspecific effects, including neutralization of negative external surface charge and inhibition of other time- and voltage-dependent ionic currents.
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Qu, Lintao, Kai Fu, Steven G. Shimada, and Robert H. LaMotte. "Cl− channel is required for CXCL10-induced neuronal activation and itch response in a murine model of allergic contact dermatitis." Journal of Neurophysiology 118, no. 1 (July 1, 2017): 619–24. http://dx.doi.org/10.1152/jn.00187.2017.
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Persistent itch often accompanies allergic contact dermatitis (ACD), but the underlying mechanisms remain largely unexplored. We previously demonstrated that CXCL10/CXCR3 signaling activated a subpopulation of cutaneous primary sensory neurons and mediated itch response after contact hypersensitivity (CHS), a murine model of ACD, induced by squaric acid dibutylester. The purpose of this study was to determine the ionic mechanisms underlying CXCL10-induced neuronal activation and allergic itch. In whole cell recordings, CXCL10 triggered a current in dorsal root ganglion (DRG) neurons innervating the area of CHS. This current was modulated by intracellular Cl− and blocked by the general Cl− channel inhibitors. Moreover, increasing Ca2+ buffering capacity reduced this current. In addition, blockade of Cl− channels significantly suppressed CXCL10-induced Ca2+ response. In behavioral tests, injection of CXCL10 into CHS site exacerbated itch-related scratching behaviors. Moreover, the potentiating behavioral effects of CXCL10 were attenuated by either of two Cl− channel blockers. Thus we suggest that the Cl− channel acts as a downstream target mediating the excitatory and pruritic behavioral effects of CXCL10. Cl− channels may provide a promising therapeutic target for the treatment of allergic itch in which CXCL10/CXCR3 signaling may participate. NEW & NOTEWORTHY The ionic mechanisms underlying CXCL10-induced neuronal activation and allergic itch are largely unexplored. This study revealed that CXCL10 evoked an ionic current mainly carried by Cl− channels. We suggest that Cl− channels are likely key molecular candidates responsible for the CXCL10-evoked neuronal activation and itch-like behaviors in a murine model of allergic contact dermatitis induced by the antigen squaric acid dibutylester. Cl− channels may emerge as a promising drug target for the treatment of allergic itch in which CXCL10/CXCR3 signaling may participate.
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Gao, J., R. T. Mathias, I. S. Cohen, and G. J. Baldo. "Two functionally different Na/K pumps in cardiac ventricular myocytes." Journal of General Physiology 106, no. 5 (November 1, 1995): 995–1030. http://dx.doi.org/10.1085/jgp.106.5.995.
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The whole-cell patch-clamp technique was used to voltage clamp acutely isolated myocytes at -60 mV and study effects of ionic environment on Na/K pump activity. In quiescent guinea pig myocytes, normal intracellular Na+ is approximately 6 mM, which gives a total pump current of 0.25 +/- 0.09 pA/pF, and an inward background sodium current of 0.75 +/- 0.26 pA/pF. The average capacitance of a cell is 189 +/- 61 pF. Our main conclusion is the total Na/K pump current comprises currents from two different types of pumps, whose functional responses to the extracellular environment are different. Pump current was reversibly blocked with two affinities by extracellular dihydro-ouabain (DHO). We determined dissociation constants of 72 microM for low affinity (type-1) pumps and 0.75 microM for high affinity (type-h) pumps. These dissociation constants did not detectably change with two intracellular Na+ concentrations, one saturating and one near half-saturating, and with two extracellular K+ concentrations of 4.6 and 1.0 mM. Ion effects on type-h pumps were therefore measured using 5 microM DHO and on total pump current using 1 mM DHO. Extracellular K+ half-maximally activated the type-h pumps at 0.4 mM and the type-1 at 3.7 mM. Extracellular H+ blocked the type-1 pumps with half-maximal blockade at a pH of 7.71 whereas the type-h pumps were insensitive to extracellular pH. Both types of pumps responded similarly to changes in intracellular-Na+, with 9.6 mM causing half-maximal activation. Neither changes in intracellular pH between 6.0 and 7.2, nor concentrations of intracellular K+ of 140 mM or below, had any effect on either type of pump. The lack of any effect of intracellular K+ suggests the dissociation constants are in the molar range so this step in the pump cycle is not rate limiting under normal physiological conditions. Changes in intracellular-Na+ did not affect the half-maximal activation by extracellular K+, and vice versa. We found DHO-blockade of Na/K pump current in canine ventricular myocytes also occurred with two affinities, which are very similar to those from guinea pig myocytes or rat ventricular myocytes. In contrast, isolated canine Purkinje myocytes have predominantly the type-h pumps, insofar as DHO-blockade and extracellular K+ activation are much closer to our type-h results than type-1. These observations suggest for mammalian ventricular myocytes: (a) the presence of two types of Na/K pumps may be a general property. (b) Normal physiological variations in extracellular pH and K+ are important determinants of Na/K pump current. (c) Normal physiological variations in the intracellular environment affect Na/K pump current primarily via the Na+ concentration. Lastly, Na/K pump current appears to be specifically tailored for a tissue by expression of a mix of functionally different types of pumps.
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Pape, Hans-Christian, and Robert B. Driesang. "Ionic Mechanisms of Intrinsic Oscillations in Neurons of the Basolateral Amygdaloid Complex." Journal of Neurophysiology 79, no. 1 (January 1, 1998): 217–26. http://dx.doi.org/10.1152/jn.1998.79.1.217.
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Pape, Hans-Christian and Robert B. Driesang. Ionic mechanisms of intrinsic oscillations in neurons of the basolateral amygdaloid complex. J. Neurophysiol. 79: 217–226, 1998. Ionic mechanisms underlying low-threshold (LTO) and high-threshold (HTO) oscillations occurring in a class of spiny neurons within the basolateral amygdaloid complex (see companion paper) were investigated in slice preparations of the guinea pig amygdala in vitro. LTOs were abolished through local application of tetrodotoxin (TTX, 10–20 μM) or a decrease in the extracellular sodium concentration ([Na+]o) from 153 to 26 mM, whereas HTOs were more readily elicited under these conditions. The effects of TTX and low [Na+]o were accompanied by a hyperpolarizing shift of the membrane potential by 3 ± 1 mV and a decrease in apparent input resistance by 14 ± 11 MΩ. LTOs were not observed during intracellular recording with QX 314 (50 μM) or Cs-acetate (2 M) containing micropipettes. At membrane potentials associated with LTO generation, voltage responses to sinusoidal current input with changing frequency between 0 and 10 Hz were characterized by a peak in the response (resonance) at 2.4 ± 1 Hz, largely corresponding to the frequency range of the LTOs. Resonance behavior was evident as a peak in the impedance amplitude plot ( ZA-plot) and a maximum in the fast Fourier transformation (FFT). Resonance and LTOs were concomitantly reduced by TTX and barium (Ba2+;2–10 mM) and were preserved during action of extracellular cesium (Cs+; 10–30 mM) or tetraethylammonium chloride (TEA; 20–50 mM), although the peak in the frequency domain tended to shift to lower values in TEA. Application of carbachol (50–200 μM) significantly reduced or blocked LTOs, whereas 4-aminopyridine (4-AP; 10 mM), iberiotoxin (Ibtx, 10 μM), and apamin (20 μM) had no effect. Slow depolarizing/repolarizing current ramps (12.5–125 pA/s) evoked HTOs as rhythmic deflections in membrane potential at either phase of the current ramp. Substitution of extracellular calcium (Ca2+) by magnesium and addition of cobalt chloride (2–4 mM) blocked HTOs but had no measurable effect on the propensity of the cells to produce LTOs. HTOs were abolished within ∼10 min after impalement of the cells with a bis-(2-aminophenoxy)- N,N,N′,N′-tetraacetic acid (BAPTA; 200 mM)–containing micropipette. Intracellular Cs+, extracellular Ba2+ (2–10 mM), or extracellular TEA (20–50 mM) induced an increase in amplitude of the rhythmic discharges and an increasingly slowed time course of repolarization at successive oscillatory events, until a steady depolarization was reached at −20 to −10 mV. Application of Ibtx (10 μM) reversibly abolished rhythmic activity during the repolarizing phase of the current ramp, whereas charybdotoxin (2–10 μM) and apamin (20 μM) had no effect. Changes in the chloride (Cl−) equilibrium potential by approximately +30 mV through intracellular recording with a KNO3 (3 M)–containing micropipette or lowering [Cl−]o from 128 to 4 mM, or blockade of Cl− conductances through niflumic acid (100 μM), did not significantly effect LTOs or HTOs. The generation of repetitive spike patterns on membrane depolarization was substantially influenced through removal of extracellular Ca2+ and associated blockade of HTOs, in that the initial high frequent discharge was abolished, frequency adaptation toward slow-rhythmic firing was delayed, and firing occurred at a more irregular pattern during strong depolarizing stimuli. It is concluded that a TTX-sensitive Na+ conductance and the M current contribute to generation of the LTOs, although their exact role in rhythmogenesisremains to be determined. HTOs seem to largely depend on a functional coupling between high-voltage–activated Ca2+ conductances, a Ca2+-activated K+ current presumably carried through BKCa channels, and additional voltage-dependent K+ conductances. In functional terms, the HTOs are important in determining spike frequency adaptation toward a slow-rhythmic firing pattern during maintained depolarizing influence.
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Botchkin, L. M., and G. Matthews. "Chloride current activated by swelling in retinal pigment epithelium cells." American Journal of Physiology-Cell Physiology 265, no. 4 (October 1, 1993): C1037—C1045. http://dx.doi.org/10.1152/ajpcell.1993.265.4.c1037.
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A membrane conductance activated by cell swelling was characterized in cells of the retinal pigment epithelium (RPE). Manipulations of internal and external Cl concentration revealed that the conductance is permeable to Cl and somewhat permeable to the gluconate anion used for Cl substitution (ratio of gluconate to Cl permeability approximately 0.1). The conductance was blocked by the Cl channel blockers 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid and 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid in a manner consistent with open-channel blockade. Both the onset and recovery of the Cl current following a transient increase in cell volume were slow. This suggests that activation of the current depends on some internal signal rather than directly on membrane stretch. Experiments to examine a possible role for intracellular Ca concentration ([Ca]i) in regulation of the current demonstrated that an increase in [Ca]i was not involved in the linkage between swelling and Cl current; activation of the current was unaffected by the calcium-buffering conditions, the current could not be activated by large increases in [Ca]i elicited by ionomycin, and no changes in [Ca]i were observed to be associated with swelling. RPE cells normally experience changes in the volume and ionic composition of the extracellular subretinal space during changes in illumination conditions; therefore, the volume-sensitive Cl conductance may play a role in volume regulation in the RPE in response to these extracellular changes and/or in transepithelial fluid transport.
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Bradler, Cathleen, Ben Warren, Viktor Bardos, Sabine Schleicher, Andreas Klein, and Peter Kloppenburg. "Properties and physiological function of Ca2+-dependent K+ currents in uniglomerular olfactory projection neurons." Journal of Neurophysiology 115, no. 5 (May 1, 2016): 2330–40. http://dx.doi.org/10.1152/jn.00840.2015.
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Ca2+-activated potassium currents [ IK(Ca)] are an important link between the intracellular signaling system and the membrane potential, which shapes intrinsic electrophysiological properties. To better understand the ionic mechanisms that mediate intrinsic firing properties of olfactory uniglomerular projection neurons (uPNs), we used whole cell patch-clamp recordings in an intact adult brain preparation of the male cockroach Periplaneta americana to analyze IK(Ca). In the insect brain, uPNs form the principal pathway from the antennal lobe to the protocerebrum, where centers for multimodal sensory processing and learning are located. In uPNs the activation of IK(Ca) was clearly voltage and Ca2+ dependent. Thus under physiological conditions IK(Ca) is strongly dependent on Ca2+ influx kinetics and on the membrane potential. The biophysical characterization suggests that IK(Ca) is generated by big-conductance (BK) channels. A small-conductance (SK) channel-generated current could not be detected. IK(Ca) was sensitive to charybdotoxin (CTX) and iberiotoxin (IbTX) but not to apamin. The functional role of IK(Ca) was analyzed in occlusion experiments under current clamp, in which portions of IK(Ca) were blocked by CTX or IbTX. Blockade of IK(Ca) showed that IK(Ca) contributes significantly to intrinsic electrophysiological properties such as the action potential waveform and membrane excitability.
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Saito, Yasuhiko, and Yuchio Yanagawa. "Ca2+-activated ion currents triggered by ryanodine receptor-mediated Ca2+release control firing of inhibitory neurons in the prepositus hypoglossi nucleus." Journal of Neurophysiology 109, no. 2 (January 15, 2013): 389–404. http://dx.doi.org/10.1152/jn.00617.2012.
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Spontaneous miniature outward currents (SMOCs) are known to exist in smooth muscles and peripheral neurons, and evidence for the presence of SMOCs in central neurons has been accumulating. SMOCs in central neurons are induced through Ca2+-activated K+(KCa) channels, which are activated through Ca2+-induced Ca2+release from the endoplasmic reticulum via ryanodine receptors (RyRs). Previously, we found that some neurons in the prepositus hypoglossi nucleus (PHN) showed spontaneous outward currents (SOCs). In the present study, we used whole cell recordings in slice preparations of the rat brain stem to investigate the following: 1) the ionic mechanisms of SOCs, 2) the types of neurons exhibiting frequent SOCs, and 3) the effect of Ca2+-activated conductance on neuronal firing. Pharmacological analyses revealed that SOCs were induced via the activation of small-conductance-type KCa(SK) channels and RyRs, indicating that SOCs correspond to SMOCs. An analysis of the voltage responses to current pulses of the fluorescence-expressing inhibitory neurons of transgenic rats revealed that inhibitory neurons frequently exhibited SOCs. Abolition of SOCs via blockade of SK channels enhanced the frequency of spontaneous firing of inhibitory PHN neurons. However, abolition of SOCs via blockade of RyRs reduced the firing frequency and hyperpolarized the membrane potential. Similar reductions in firing frequency and hyperpolarization were also observed when Ca2+-activated nonselective cation (CAN) channels were blocked. These results suggest that, in inhibitory neurons in the PHN, Ca2+release via RyRs activates SK and CAN channels, and these channels regulate spontaneous firing in a complementary manner.
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Franceschetti, Silvana, Tatiana Lavazza, Giulia Curia, Patrizia Aracri, Ferruccio Panzica, Giulio Sancini, Giuliano Avanzini, and Jacopo Magistretti. "Na+-Activated K+ Current Contributes to Postexcitatory Hyperpolarization in Neocortical Intrinsically Bursting Neurons." Journal of Neurophysiology 89, no. 4 (April 1, 2003): 2101–11. http://dx.doi.org/10.1152/jn.00695.2002.
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The ionic mechanisms underlying the termination of action-potential (AP) bursts and postburst afterhyperpolarization (AHP) in intrinsically bursting (IB) neocortical neurons were investigated by performing intracellular recordings in thin slices of rat sensorimotor cortex. The blockade of Ca2+-activated K+currents enhanced postburst depolarizing afterpotentials, but had inconsistent and minor effects on the amplitude and duration of AHPs. On the contrary, experimental conditions resulting in reduction of voltage-dependent Na+ entry into the cells caused a significant decrease of AHP amplitude. Slice perfusion with a modified artificial cerebrospinal fluid in which LiCl (40 mM) partially replaced NaCl had negligible effects on the properties of individual APs, whereas it consistently increased burst length and led to an approximately 30% reduction in the amplitude of AHPs following individual bursts or short trains of stimulus-induced APs. Experiments performed by partially replacing Na+ ions with choline revealed a comparable reduction in AHP amplitude associated with an inhibition of bursting activity. Moreover, in voltage-clamp experiments carried out in both in situ and acutely isolated neurons, partial substitution of extracellular NaCl with LiCl significantly and reversibly reduced the amplitude of K+ currents evoked by depolarizing stimuli above-threshold for Na+-current activation. The above effect of Na+-to-Li+substitution was not seen when voltage-gated Na+ currents were blocked with TTX, indicating the presence of a specific K+-current component activated by voltage-dependent Na+ (but not Li+) influx. The above findings suggest that a Na+-activated K+ current recruited by the Na+ entry secondary to burst discharge significantly contributes to AHP generation and the maintenance of rhythmic burst recurrence during sustained depolarizations in neocortical IB neurons.
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Yokota, Kazumichi, Asae Takeo, Hiroko Abe, Yuji Kurokawa, Muneaki Hashimoto, Kazuaki Kajimoto, Masato Tanaka, et al. "Application of Micropore Device for Accurate, Easy, and Rapid Discrimination of Saccharomyces pastorianus from Dekkera spp." Biosensors 11, no. 8 (August 12, 2021): 272. http://dx.doi.org/10.3390/bios11080272.
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Traceability analysis, such as identification and discrimination of yeasts used for fermentation, is important for ensuring manufacturing efficiency and product safety during brewing. However, conventional methods based on morphological and physiological properties have disadvantages such as time consumption and low sensitivity. In this study, the resistive pulse method (RPM) was employed to discriminate between Saccharomyces pastorianus and Dekkera anomala and S. pastorianus and D. bruxellensis by measuring the ionic current response of cells flowing through a microsized pore. The height and shape of the pulse signal were used for the simultaneous measurement of the size, shape, and surface charge of individual cells. Accurate discrimination of S. pastorianus from Dekkera spp. was observed with a recall rate of 96.3 ± 0.8%. Furthermore, budding S. pastorianus was quantitatively detected by evaluating the shape of the waveform of the current ionic blockade. We showed a proof-of-concept demonstration of RPM for the detection of contamination of Dekkera spp. in S. pastorianus and for monitoring the fermentation of S. pastorianus through the quantitative detection of budding cells.
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Zhang, L., T. A. Valiante, and P. L. Carlen. "Contribution of the low-threshold T-type calcium current in generating the post-spike depolarizing afterpotential in dentate granule neurons of immature rats." Journal of Neurophysiology 70, no. 1 (July 1, 1993): 223–31. http://dx.doi.org/10.1152/jn.1993.70.1.223.
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1. The underlying ionic mechanisms of the postspike depolarizing afterpotential (DAP) in hippocampal dentate granule (DG) neurons of immature rats (postnatal 7- to 17-day-old) were examined using whole cell patch recordings in brain slices. 2. In current-clamp mode, the DAP followed each single action potential. Graded DAP-like responses were also evoked by depolarizing current pulses when the action potential was blocked by tetrodotoxin (TTX), demonstrating that the TTX-sensitive Na+ conductance is not necessary for DAP generation. The membrane resistance near the DAP peak was lower than at rest, suggesting activation of inward currents rather than blockade of outward currents during the DAP. The DAP peak amplitude showed a strong dependence on voltage, increasing with membrane hyperpolarization and decreasing with depolarization in the range of -90 to -50 mV. Repetitive stimulation at 1-2 Hz did not change the amplitude or decay of the DAP or DAP-like response. 3. Bath application of 2 mM 4-aminopyridine (4-AP) and 5 mM tetraethylammonium chloride (TEA) prolonged the action potential and enhanced the DAP, suggesting that the DAP waveform is determined by the interaction of voltage-activated outward K+ currents and inward currents. 4. Bath application of 2 mM Co2+ depressed the DAP and the DAP-like potential. Replacement of extracellular Ca2+ with Ba2+ potentiated the DAP. Intracellular Ca2+ chelation with the fast chelator, bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic acid (BAPTA), only slightly enhanced the DAP, suggesting that the DAP is not generated by inward currents activated secondary to Ca2+ influx.(ABSTRACT TRUNCATED AT 250 WORDS)
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Wu, J., and P. B. Corr. "Palmitoyl carnitine modifies sodium currents and induces transient inward current in ventricular myocytes." American Journal of Physiology-Heart and Circulatory Physiology 266, no. 3 (March 1, 1994): H1034—H1046. http://dx.doi.org/10.1152/ajpheart.1994.266.3.h1034.
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Long-chain acylcarnitines increase within 2 min in ischemic myocardium in vivo and induce delayed afterdepolarizations (DADs) and complex oscillations of membrane potential in vitro. This study was performed to assess the ionic currents underlying these electrophysiological alterations in isolated rabbit ventricular cells using whole cell voltage-clamp procedures. Palmitoyl carnitine (10 microM, for 6-10 min) elicited a transient inward current (Iti) in the presence of blockade of Ca2+ and K+ channels. The effect of palmitoyl carnitine was reversible after washout (n = 6). The amplitude of Iti was dependent on the amplitude of the preceding depolarization step. Palmitoyl carnitine (10 microM, for > 2 min) also induced another inward current, which was activated spontaneously at potentials between -120 and -20 mV with a linear current-voltage relationship (1.0 +/- 0.1 nA at -80 mV). This current was abolished by replacing extracellular Na+ with tetraethylammonium chloride, indicating that Na+ was the charge carrier. Inactivation of this current was slow (gamma = 885.9 +/- 89.1 ms, n = 12) or incomplete, indicating the appearance of a slow-inactivating Na+ inward current [INa(s)]. Palmitoyl carnitine always induced INa(s) before the appearance of Iti. Intracellular ethylene glycol-bis(beta-amino-ethyl ether)-N,N,N',N'-tetraacetic acid (10 mM) abolished Iti but did not suppress INa(s) (n = 4), indicating that INa(s) was not activated by intracellular Ca2+ (Cai2+). Tetrodotoxin (10 microM) also decreased the amplitude of INa(s). Thus palmitoyl carnitine induces INa(s), which likely leads to an increase in Na+ influx, thereby eliciting an increase in Cai2+ via the Na(+)-Ca2+ exchanger and leading to the development of Iti, DADs, and triggered activity.
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Tell, F., and R. M. Bradley. "Whole-cell analysis of ionic currents underlying the firing pattern of neurons in the gustatory zone of the nucleus tractus solitarii." Journal of Neurophysiology 71, no. 2 (February 1, 1994): 479–92. http://dx.doi.org/10.1152/jn.1994.71.2.479.
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1. Previous work from this laboratory has shown that rostral nucleus tractus solitarii (rNTS) neurons can be separated into four different classes on the basis of responses to a current injection paradigm consisting of membrane hyperpolarization immediately followed by a depolarizing pulse. These classes have been termed Group I, II, III, and IV neurons. The regular repetitive firing discharge pattern of Group I cells is changed into an irregular spike train by membrane hyperpolarization. Hyperpolarization of Group II neurons delays the firing discharge induced by depolarization. Hyperpolarization had the least effect on the discharge pattern of Group III neurons. The discharge pattern of Group IV neurons consisted of a short burst of spikes. We used whole-cell recordings and pharmacological channel blockers in an in vitro brain stem slice preparation to determine the ionic basis for the repetitive firing properties of rNTS neurons. 2. Application of 4-aminopyridine (4-AP, 1 mM) decreased input resistance and increased action potential duration in all groups of neurons. However, the discharge pattern of Group I, III, and IV neurons was either unaltered or slightly modified by 4-AP. In contrast the delay in firing of Group II cells induced by hyperpolarization was strongly reduced and in some cases completely suppressed by application of 4-AP. This suggests that a 4-AP-sensitive conductance primarily underlies the firing pattern of Group II cells. 3. Voltage-clamp recordings revealed that the delay in Group II neurons is due to a transient outward potassium current that is partially inactivated around the resting membrane potential. Hyperpolarization removed this inactivation, causing a delay in the firing of the cell. The potassium current was blocked by 4-AP. A similar current was occasionally seen in neurons of the other groups. On the basis of its voltage and pharmacological dependence this current was presumed to be an A-current (IKA). 4. Blockade of calcium currents by a low-calcium (0.5 mM) saline containing 2 mM Co2+ depressed the excitability of rNTS cells. For Group II neurons the delay in firing activity was increased. In the other groups the repetitive firing pattern was suppressed. In addition the amplitude of the afterhyperpolarization occurring after a short train of action potentials was substantially reduced. This indicates that calcium currents (ICa) and calcium-activated potassium currents (IKCa) contribute to the repetitive firing properties of rNTS neurons. 5. In about half of Group I, III, and IV neurons an additional property was found.(ABSTRACT TRUNCATED AT 400 WORDS)
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García-Díaz, J. F. "Whole-cell and single channel K+ and Cl- currents in epithelial cells of frog skin." Journal of General Physiology 98, no. 1 (July 1, 1991): 131–61. http://dx.doi.org/10.1085/jgp.98.1.131.
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Whole-cell and single channel currents were studied in cells from frog (R. pipiens and R. catesbiana) skin epithelium, isolated by collagenase and trypsin treatment, and kept in primary cultures up to three days. Whole-cell currents did not exhibit any significant time-dependent kinetics under any ionic conditions used. With an external K gluconate Ringer solution the currents showed slight inward rectification with a reversal potential near zero and an average conductance of 5 nS at reversal. Ionic substitution of the external medium showed that most of the cell conductance was due to K and that very little, if any, Na conductance was present. This confirmed that most cells originate from inner epithelial layers and contain membranes with basolateral properties. At voltages more positive than 20 mV outward currents were larger with K in the medium than with Na or N-methyl-D-glucamine. Such behavior is indicative of a multi-ion transport mechanism. Whole-cell K current was inhibited by external Ba and quinidine. Blockade by Ba was strongly voltage dependent, while that by quinidine was not. In the presence of high external Cl, a component of outward current that was inhibited by the anion channel blocker diphenylamine-2-carboxylate (DPC) appeared in 70% of the cells. This component was strongly outwardly rectifying and reversed at a potential expected for a Cl current. At the single channel level the event most frequently observed in the cell-attached configuration was a K channel with the following characteristics: inward-rectifying I-V relation with a conductance (with 112.5 mM K in the pipette) of 44 pS at the reversal potential, one open and at least two closed states, and open probability that increased with depolarization. Quinidine blocked by binding in the open state and decreasing mean open time. Several observations suggest that this channel is responsible for most of the whole-cell current observed in high external K, and for the K conductance of the basolateral membrane of the intact epithelium. On a few occasions a Cl channel was observed that activated upon excision and brief strong depolarization. The I-V relation exhibited strong outward rectification with a single channel conductance of 48 pS at 0 mV in symmetrical 112 mM Cl solutions. Kinetic analysis showed the presence of two open and at least two closed states. Open time constants and open probability increased markedly with depolarization.(ABSTRACT TRUNCATED AT 400 WORDS)
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Lai, Xiao-Gang, Jun Yang, Shi-Sheng Zhou, Jun Zhu, Gui-Rong Li, and Tak-Ming Wong. "Involvement of anion channel(s) in the modulation of the transient outward K+ channel in rat ventricular myocytes." American Journal of Physiology-Cell Physiology 287, no. 1 (July 2004): C163—C170. http://dx.doi.org/10.1152/ajpcell.00297.2003.
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The cardiac Ca2+-independent transient outward K+ current ( Ito), a major repolarizing ionic current, is markedly affected by Cl− substitution and anion channel blockers. We reexplored the mechanism of the action of anions on Ito by using whole cell patch-clamp in single isolated rat cardiac ventricular myocytes. The transient outward current was sensitive to blockade by 4-aminopyridine (4-AP) and was abolished by Cs+ substitution for intracellular K+. Replacement of most of the extracellular Cl− with less permeant anions, aspartate (Asp−) and glutamate (Glu−), markedly suppressed the current. Removal of external Na+ or stabilization of F-actin with phalloidin did not significantly affect the inhibitory action of less permeant anions on Ito. In contrast, the permeant Cl− substitute Br− did not markedly affect the current, whereas F− substitution for Cl− induced a slight inhibition. The Ito elicited during Br− substitution for Cl− was also sensitive to blockade by 4-AP. The ability of Cl− substitutes to induce rightward shifts of the steady-state inactivation curve of Ito was in the following sequence: NO3− > Cl− ≈ Br− > gluconate− > Glu− > Asp−. Depolymerization of actin filaments with cytochalasin D (CytD) induced an effect on the steady-state inactivation of Ito similar to that of less permeant anions. Fluorescent phalloidin staining experiments revealed that CytD-pretreatment significantly decreased the intensity of FITC-phalloidin staining of F-actin, whereas Asp− substitution for Cl− was without significant effect on the intensity. These results suggest that the Ito channel is modulated by anion channel(s), in which the actin cytoskeleton may be implicated.
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Sovari, Ali A. "Cellular and Molecular Mechanisms of Arrhythmia by Oxidative Stress." Cardiology Research and Practice 2016 (2016): 1–7. http://dx.doi.org/10.1155/2016/9656078.
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Current therapies for arrhythmia using ion channel blockade, catheter ablation, or an implantable cardioverter defibrillator have limitations, and it is important to search for new antiarrhythmic therapeutic targets. Both atrial fibrillation and heart failure, a condition with increased arrhythmic risk, are associated with excess amount of reactive oxygen species (ROS). There are several possible ways for ROS to induce arrhythmia. ROS can cause focal activity and reentry. ROS alter multiple cardiac ionic currents. ROS promote cardiac fibrosis and impair gap junction function, resulting in reduced myocyte coupling and facilitation of reentry. In order to design effective antioxidant drugs for treatment of arrhythmia, it is essential to explore the molecular mechanisms by which ROS exert these arrhythmic effects. Activation of Ca2+/CaM-dependent kinase II, c-Src tyrosine kinase, protein kinase C, and abnormal splicing of cardiac sodium channels are among the recently discovered molecular mechanisms of ROS-induced arrhythmia.
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Lansman, J. B. "Blockade of current through single calcium channels by trivalent lanthanide cations. Effect of ionic radius on the rates of ion entry and exit." Journal of General Physiology 95, no. 4 (April 1, 1990): 679–96. http://dx.doi.org/10.1085/jgp.95.4.679.
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Currents flowing through single dihydropyridine-sensitive Ca2+ channels were recorded from cell-attached patches on C2 myotubes. In the presence of dihydropyridine agonist to prolong the duration of single-channel openings, adding micromolar concentrations of lanthanum (La), cerium (Ce), neodymium (Nd), gadolinium (Gd), dysprosium (Dy), or ytterbium (Yb) to patch electrodes containing 110 mM BaCl2 caused the unitary Ba2+ currents to fluctuate between fully open and shut states. The kinetics of channel blockade followed the predictions of a simple open channel block model in which the fluctuations of the single-channel current arose from the entry and exit of blocking ions from the pore. Entry rates for all the lanthanides tested were relatively insensitive to membrane potential, however, exit rates depended strongly on membrane potential increasing approximately e-fold per 23 mV with hyperpolarization. Individual lanthanide ions differed in both the absolute rates of ion entry and exit: entry rates decreased as cationic radius decreased; exit rates also decreased with cationic radius during the first part of the lanthanide series but then showed little change during the latter part of the series. Overall, the results support the idea that smaller ions enter the channel more slowly, presumably because they dehydrate more slowly; smaller ions also bind more tightly to a site within the channel pore, but lanthanide residence time within the channel approaches a maximum for the smaller cations with radii less than or equal to that of Ca2+.
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Chapman, C. Andrew, and Jean-Claude Lacaille. "Intrinsic Theta-Frequency Membrane Potential Oscillations in Hippocampal CA1 Interneurons of Stratum Lacunosum-Moleculare." Journal of Neurophysiology 81, no. 3 (March 1, 1999): 1296–307. http://dx.doi.org/10.1152/jn.1999.81.3.1296.
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Intrinsic theta-frequency membrane potential oscillations in hippocampal CA1 interneurons of stratum lacunosum-moleculare. The ionic conductances underlying membrane potential oscillations of hippocampal CA1 interneurons located near the border between stratum lacunosum-moleculare and stratum radiatum (LM) were investigated using whole cell current-clamp recordings in rat hippocampal slices. At 22°C, when LM cells were depolarized near spike threshold by current injection, 91% of cells displayed 2–5 Hz oscillations in membrane potential, which caused rhythmic firing. At 32°C, mean oscillation frequency increased to 7.1 Hz. Oscillations were voltage dependent and were eliminated by hyperpolarizing cells 6–10 mV below spike threshold. Blockade of ionotropic glutamate and GABA synaptic transmission did not affect oscillations, indicating that they were not synaptically driven. Oscillations were eliminated by tetrodotoxin, suggesting that Na+ currents generate the depolarizing phase of oscillations. Oscillations were not affected by blocking Ca2+ currents with Cd2+ or Ca2+-free ACSF or by blocking the hyperpolarization-activated current ( I h) with Cs+. Both Ba2+ and a low concentration of 4-aminopyridine (4-AP) reduced oscillations but TEA did not. Theta-frequency oscillations were much less common in interneurons located in stratum oriens. Intrinsic membrane potential oscillations in LM cells of the CA1 region thus involve an interplay between inward Na+ currents and outward K+ currents sensitive to Ba2+ and 4-AP. These oscillations may participate in rhythmic inhibition and synchronization of pyramidal neurons during theta activity in vivo.
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Boehlen, Anne, Christian Henneberger, Uwe Heinemann, and Irina Erchova. "Contribution of near-threshold currents to intrinsic oscillatory activity in rat medial entorhinal cortex layer II stellate cells." Journal of Neurophysiology 109, no. 2 (January 15, 2013): 445–63. http://dx.doi.org/10.1152/jn.00743.2011.
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The temporal lobe is well known for its oscillatory activity associated with exploration, navigation, and learning. Intrinsic membrane potential oscillations (MPOs) and resonance of stellate cells (SCs) in layer II of the entorhinal cortex are thought to contribute to network oscillations and thereby to the encoding of spatial information. Generation of both MPOs and resonance relies on the expression of specific voltage-dependent ion currents such as the hyperpolarization-activated cation current ( IH), the persistent sodium current ( INaP), and the noninactivating muscarine-modulated potassium current ( IM). However, the differential contributions of these currents remain a matter of debate. We therefore examined how they modify neuronal excitability near threshold and generation of near-threshold MPOs and resonance in vitro. We found that resonance mainly relied on IH and was reduced by IH blockers and modulated by cAMP and an IM enhancer but that neither of the currents exhibited full control over MPOs in these cells. As previously reported, IH controlled a theta-frequency component of MPOs such that blockade of IH resulted in fewer regular oscillations that retained low-frequency components and high peak amplitude. However, pharmacological inhibition and augmentation of IM also affected MPO frequencies and amplitudes. In contrast to other cell types, inhibition of INaP did not result in suppression of MPOs but only in a moderation of their properties. We reproduced the experimentally observed effects in a single-compartment stochastic model of SCs, providing further insight into the interactions between different ionic conductances.
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Jiang, Jianmin, Mingjiang Li, and Lixia Yue. "Potentiation of TRPM7 Inward Currents by Protons." Journal of General Physiology 126, no. 2 (July 11, 2005): 137–50. http://dx.doi.org/10.1085/jgp.200409185.
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TRPM7 is unique in being both an ion channel and a protein kinase. It conducts a large outward current at +100 mV but a small inward current at voltages ranging from −100 to −40 mV under physiological ionic conditions. Here we show that the small inward current of TRPM7 was dramatically enhanced by a decrease in extracellular pH, with an ∼10-fold increase at pH 4.0 and 1–2-fold increase at pH 6.0. Several lines of evidence suggest that protons enhance TRPM7 inward currents by competing with Ca2+ and Mg2+ for binding sites, thereby releasing blockade of divalent cations on inward monovalent currents. First, extracellular protons significantly increased monovalent cation permeability. Second, higher proton concentrations were required to induce 50% of maximal increase in TRPM7 currents when the external Ca2+ and Mg2+ concentrations were increased. Third, the apparent affinity for Ca2+ and Mg2+ was significantly diminished at elevated external H+ concentrations. Fourth, the anomalous-mole fraction behavior of H+ permeation further suggests that protons compete with divalent cations for binding sites in the TRPM7 pore. Taken together, it appears that at physiological pH (7.4), Ca2+ and Mg2+ bind to TRPM7 and inhibit the monovalent cationic currents; whereas at high H+ concentrations, the affinity of TRPM7 for Ca2+ and Mg2+ is decreased, thereby allowing monovalent cations to pass through TRPM7. Furthermore, we showed that the endogenous TRPM7-like current, which is known as Mg2+-inhibitable cation current (MIC) or Mg nucleotide–regulated metal ion current (MagNuM) in rat basophilic leukemia (RBL) cells was also significantly potentiated by acidic pH, suggesting that MIC/MagNuM is encoded by TRPM7. The pH sensitivity represents a novel feature of TRPM7 and implies that TRPM7 may play a role under acidic pathological conditions.
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Panek, Izabela, Ulli Höger, Andrew S. French, and Päivi H. Torkkeli. "Contributions of Voltage- and Ca2+-Activated Conductances to GABA-Induced Depolarization in Spider Mechanosensory Neurons." Journal of Neurophysiology 99, no. 4 (April 2008): 1596–606. http://dx.doi.org/10.1152/jn.01267.2007.
Full textAbstract:
Activation of ionotropic γ-aminobutyric acid type A (GABAA) receptors depolarizes neurons that have high intracellular [Cl−], causing inhibition or excitation in different cell types. The depolarization often leads to inactivation of voltage-gated Na channels, but additional ionic mechanisms may also be affected. Previously, a simulated model of spider VS-3 mechanosensory neurons suggested that although voltage-activated Na+ current is partially inactivated during GABA-induced depolarization, a slowly activating and inactivating component remains and may contribute to the depolarization. Here, we confirmed experimentally, by blocking Na channels prior to GABA application, that Na+ current contributes to GABA-induced depolarization in VS-3 neurons. Ratiometric Ca2+ imaging experiments combined with intracellular recordings revealed a significant increase in intracellular [Ca2+] when GABAA receptors were activated, synchronous with the depolarization and probably due to Ca2+ influx via low-voltage–activated (LVA) Ca channels. In contrast, GABAB-receptor activation in these neurons was previously shown to inhibit LVA current. Blockade of voltage-gated K channels delayed membrane repolarization, extending GABA-induced depolarization. However, inhibition of Ca channels significantly increased the amplitude of GABA-induced depolarization, indicating that Ca2+-activated K+ current has an even stronger repolarizing effect. Regulation of intracellular [Ca2+] is important for many cellular processes and Ca2+ control of K+ currents may be particularly important for some functions of mechanosensory neurons, such as frequency tuning. These data show that GABAA-receptor activation participates in this regulation.
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Jackel, C., W. Krenz, and F. Nagy. "BICUCULLINE/BACLOFEN-INSENSITIVE GABA RESPONSE IN CRUSTACEAN NEURONES IN CULTURE." Journal of Experimental Biology 191, no. 1 (June 1, 1994): 167–93. http://dx.doi.org/10.1242/jeb.191.1.167.
Full textAbstract:
Neurones were dissociated from thoracic ganglia of embryonic and adult lobsters and kept in primary culture. When gamma-aminobutyric acid (GABA) was applied by pressure ejection, depolarizing or hyperpolarizing responses were produced, depending on the membrane potential. They were accompanied by an increase in membrane conductance. When they were present, action potential firing was inhibited. The pharmacological profile and ionic mechanism of GABA-evoked current were investigated under voltage-clamp with the whole-cell patch-clamp technique. The reversal potential of GABA-evoked current depended on the intracellular and extracellular Cl- concentration but not on extracellular Na+ and K+. Blockade of Ca2+ channels by Mn2+ was also without effect. The GABA-evoked current was mimicked by application of the GABAA agonists muscimol and isoguvacine with an order of potency muscimol>GABA>isoguvacine. cis-4-aminocrotonic acid (CACA), a folded and conformationally restricted GABA analogue, supposed to be diagnostic for the vertebrate GABAC receptor, also induced a bicuculline-resistant chloride current, although with a potency about 10 times lower than that of GABA. The GABA-evoked current was largely blocked by picrotoxin, but was insensitive to the GABAA antagonists bicuculline, bicuculline methiodide and SR 95531 at concentrations of up to 100 µmol l-1. Diazepam and phenobarbital did not exert modulatory effects. The GABAB antagonist phaclophen did not affect the GABA-induced current, while the GABAB agonists baclophen and 3-aminopropylphosphonic acid (3-APA) never evoked any response. Our results suggest that lobster thoracic neurones in culture express a chloride-conducting GABA-receptor channel which conforms to neither the GABAA nor the GABAB types of vertebrates but shows a pharmacology close to that of the novel GABAC receptor described in the vertebrate retina.
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Morris, M. E., and S. Liske. "Ionic mechanisms of action of GABA on dorsal and ventral root myelinated fibers: effects of K+ channel blockers." Canadian Journal of Physiology and Pharmacology 67, no. 10 (October 1, 1989): 1308–14. http://dx.doi.org/10.1139/y89-208.
Full textAbstract:
Excitability changes evoked by the inhibitory neurotransmitter, GABA (γ-aminobutyric acid) in myelinated axons of dorsal and ventral roots of the isolated bullfrog sciatic nerve were compared in the absence and presence of K+ channel blockers. Half-maximal A-fiber responses to a 0.5-Hz stimulation of the whole nerve were recorded from individual roots. Direct applications of Ringer with raised K+ levels to the site of stimulation caused increases in excitability of both dorsal and ventral root fibers, which resembled those evoked in the ventral root by the GABA agonist THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]ol). The increases in dorsal root fiber responses produced by GABA were depressed by tetraethylammonium (TEA) (3 mM), 4-aminopyridine (4-AP) (50 μM), Cs (2 mM), and Ba (1 mM). Ventral root fibers were less consistently affected. The early component of GABA-evoked excitability increases was depressed by 4-AP, Cs, and Ba, but greatly augmented by TEA. THIP-evoked changes in the excitability of the dorsal and ventral root fibers were, respectively, depressed and enhanced by TEA. The augmenting effect of TEA on the early component of GABA agonist effects on the ventral root fibers is attributed to their high resting K+ conductance and the presence of a slowly inactivating, fast K+ current (If1). The depressant effects of K+ channel blockade on depolarizing components of agonist-evoked changes in dorsal and ventral root responses indicate interference with release and (or) sensitivity to K+ and a possible contribution from a mechanism involving voltage-dependent delayed rectifier K+ currents.Key words: K+ channel blockade, γ-aminobutyric acid agonists, K+ accumulation, K+ application, excitability.
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Poulter, M. O., T. Hashiguchi, and A. L. Padjen. "An examination of frog myelinated axons using intracellular microelectrode recording: the role of voltage-dependent and leak conductances on the steady-state electrical properties." Journal of Neurophysiology 70, no. 6 (December 1, 1993): 2301–12. http://dx.doi.org/10.1152/jn.1993.70.6.2301.
Full textAbstract:
1. Intracellular microelectrode current-clamp technique was used to study the steady-state membrane properties of single intact large primary afferent axons (conduction velocity > 10 m/s) attached to isolated hemisected frog spinal cord. 2. Hyperpolarizing electrotonic potentials (ETPs) had a slow complex multiphasic charging. This complex charging could be approximated by two time constants: one in the range of 70–210 ms, the other of < 20 ms. 3. Two regions of outward and inward rectification hyperpolarized to the resting membrane potential were observed, in addition to the previously characterized outward rectification active at potentials depolarized to resting membrane potential. The peak and steady-state input resistance of these axons in tetrodotoxin Ringer solution was on average 65.6 +/- 21.1 and 31.1 +/- 10.8 M omega, mean +/- SE, respectively. 4. Application of external tetraethylammonium (10–20 mM) significantly depolarized the axon and decreased the outward rectification just hyperpolarized to the resting membrane potential. This outward rectification could also be blocked by external barium ions (2–10 mM). 5. Activation of an inward or anomalous rectification in these axons was observed 300–600 ms after the start of a current pulse. In addition, a depolarizing afterpotential (DAP) (1–3 mV in amplitude, 500 ms-10 s in duration) was evident after a current pulse in which inward rectification had been activated. This DAP most likely reflected the slow inactivation of the inwardly rectifying conductance. 6. Inward rectification was blocked by external application of cesium ions (1–3 mM) but it was insensitive to external application of barium ions (2–10 mM). The blockade of the voltage attenuation was accompanied by a disappearance of the DAP and an increase in the charging time constant of the axon. This blockade resulted in a single linear voltage-current (V-I) relationship. Axons now had, on average, an input resistance of 114 +/- 19.1 M omega. 7. Reducing the concentration of external potassium ions increased both the peak and steady-state slope resistance. Reducing the external sodium concentration altered the ETPs and the V-I relationship little but it consistently reduced the magnitude and length of the DAP. These results are compatible with the hypothesis that anomalous rectification is a mixed ionic conductance dependent on potassium and sodium ions in the external media. 8. Overall, the V-I relationship of these intact axons had both linear and nonlinear regions reflecting the activity of numerous slowly activating and inactivating conductances. (ABSTRACT TRUNCATED AT 400 WORDS)
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Löhrke, Stefan, and Hans-Dieter Hofmann. "Voltage-gated currents of rabbit A- and B-type horizontal cells in retinal monolayer cultures." Visual Neuroscience 11, no. 2 (March 1994): 369–78. http://dx.doi.org/10.1017/s0952523800001711.
Full textAbstract:
AbstractIn monolayer cultures prepared from immature early postnatal rabbit retina, small populations of neurons can be demonstrated to differentiate into apparently mature A- and B-type horizontal cells. Using wholecell, single-channel, patch-clamp recording techniques, we have analyzed the pattern of voltage-gated conductances expressed by mammalian horizontal cells under these conditions. A total of six different voltage-dependent ionic currents were recorded. Tetrodotoxin-sensitive fast sodium inward currents (INa) were found in 81% of the A-type and 90% of the B-type cells. Inward calcium currents could be demonstrated in all cells tested after blockade of other conductances. Two types of outward potassium currents with properties of the 4–aminopyridine-sensitive transient IA and the tetraethylammonium sensitive delayed rectifier IK, respectively, could be characterized in whole-cell recordings. An inward rectifying potassium current (Ianom) typical for horizontal cells was activated in response to hyperpolarizing voltage steps. These types of currents have also been described in dissociated adult horizontal cells from lower vertebrates and cat. With single-channel recordings on inside-out patches excised from B-type cells, an additional Ca2+-dependent current (IK(Ca)) was observed which, so far, has not been described in horizontal cells developing in situ. Our results demonstrate that cultured rabbit horizontal cells express a set of voltage-gated currents which largely, but not completely, corresponds to that described in situ for horizontal cells of other species. The culture system will allow further investigation of developmental and functional aspects of mammalian horizontal cells.
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Boda, Dezső, Mónika Valiskó, Douglas Henderson, Bob Eisenberg, Dirk Gillespie, and Wolfgang Nonner. "Ionic selectivity in L-type calcium channels by electrostatics and hard-core repulsion." Journal of General Physiology 133, no. 5 (April 27, 2009): 497–509. http://dx.doi.org/10.1085/jgp.200910211.
Full textAbstract:
A physical model of selective “ion binding” in the L-type calcium channel is constructed, and consequences of the model are compared with experimental data. This reduced model treats only ions and the carboxylate oxygens of the EEEE locus explicitly and restricts interactions to hard-core repulsion and ion–ion and ion–dielectric electrostatic forces. The structural atoms provide a flexible environment for passing cations, thus resulting in a self-organized induced-fit model of the selectivity filter. Experimental conditions involving binary mixtures of alkali and/or alkaline earth metal ions are computed using equilibrium Monte Carlo simulations in the grand canonical ensemble. The model pore rejects alkali metal ions in the presence of biological concentrations of Ca2+ and predicts the blockade of alkali metal ion currents by micromolar Ca2+. Conductance patterns observed in varied mixtures containing Na+ and Li+, or Ba2+ and Ca2+, are predicted. Ca2+ is substantially more potent in blocking Na+ current than Ba2+. In apparent contrast to experiments using buffered Ca2+ solutions, the predicted potency of Ca2+ in blocking alkali metal ion currents depends on the species and concentration of the alkali metal ion, as is expected if these ions compete with Ca2+ for the pore. These experiments depend on the problematic estimation of Ca2+ activity in solutions buffered for Ca2+ and pH in a varying background of bulk salt. Simulations of Ca2+ distribution with the model pore bathed in solutions containing a varied amount of Li+ reveal a “barrier and well” pattern. The entry/exit barrier for Ca2+ is strongly modulated by the Li+ concentration of the bath, suggesting a physical explanation for observed kinetic phenomena. Our simulations show that the selectivity of L-type calcium channels can arise from an interplay of electrostatic and hard-core repulsion forces among ions and a few crucial channel atoms. The reduced system selects for the cation that delivers the largest charge in the smallest ion volume.
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Gibbs III, John W., Yun-Fu Zhang, Melissa D. Shumate, and Douglas A. Coulter. "Regionally Selective Blockade of GABAergic Inhibition by Zinc in the Thalamocortical System: Functional Significance." Journal of Neurophysiology 83, no. 3 (March 1, 2000): 1510–21. http://dx.doi.org/10.1152/jn.2000.83.3.1510.
Full textAbstract:
The thalamocortical (TC) system is a tightly coupled synaptic circuit in which GABAergic inhibition originating from the nucleus reticularis thalami (NRT) serves to synchronize oscillatory TC rhythmic behavior. Zinc is colocalized within nerve terminals throughout the TC system with dense staining for zinc observed in NRT, neocortex, and thalamus. Whole cell voltage-clamp recordings of GABA-evoked responses were conducted in neurons isolated from ventrobasal thalamus, NRT, and somatosensory cortex to investigate modulation of the GABA-mediated chloride conductance by zinc. Zinc blocked GABA responses in a regionally specific, noncompetitive manner within the TC system. The regional levels of GABA blockade efficacy by zinc were: thalamus > NRT > cortex. The relationship between clonazepam and zinc sensitivity of GABAA-mediated responses was examined to investigate possible presence or absence of specific GABAAreceptor (GABAR) subunits. These properties of GABARs have been hypothesized previously to be dependent on presence or absence of the γ2 subunit and seem to display an inverse relationship. In cross-correlation plots, thalamic and NRT neurons did not show a statistically significant relationship between clonazepam and zinc sensitivity; however, a statistically significant correlation was observed in cortical neurons. Spontaneous epileptic TC oscillations can be induced in vitro by perfusion of TC slices with an extracellular medium containing no added Mg2+. Multiple varieties of oscillations are generated, including simple TC burst complexes (sTBCs), which resemble spike-wave discharge activity. A second variant was termed a complex TC burst complex (cTBC), which resembled generalized tonic clonic seizure activity. sTBCs were exacerbated by zinc, whereas cTBCs were blocked completely by zinc. This supported the concept that zinc release may modulate TC rhythms in vivo. Zinc interacts with a variety of ionic conductances, including GABAR currents, N-methyl-d-aspartate (NMDA) receptor currents, and transient potassium (A) currents.d−2-amino-5-phosphonovaleric acid and 4-aminopyridine blocked both s- and cTBCs in TC slices. Therefore NMDA and A current-blocking effects of zinc are insufficient to explain differential zinc sensitivity of these rhythms. This supports a significant role of zinc-induced GABAR modulation in differential TC rhythm effects. Zinc is localized in high levels within the TC system and appears to be released during TC activity. Furthermore application of exogenous zinc modulates TC rhythms and differentially blocks GABARs within the TC system. These data are consistent with the hypothesis that endogenously released zinc may have important neuromodulatory actions impacting generation of TC rhythms, mediated at least in part by effects on GABARs.
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Branchereau, P., J. Champagnat, and M. Denavit-Saubie. "Cholecystokinin-gated currents in neurons of the rat solitary complex in vitro." Journal of Neurophysiology 70, no. 6 (December 1, 1993): 2584–95. http://dx.doi.org/10.1152/jn.1993.70.6.2584.
Full textAbstract:
1. Ionic conductances controlled by type A and type B cholecystokinin (CCK) receptors were studied in neurons of the rat nucleus tractus solitarius (NTS) and dorsal motor nucleus of the vagus (DMNV), using intracellular and whole-cell patch clamp recordings in current or voltage clamp configuration during bath application of agonists (CCK8, CCK4, BC 264) and antagonists. 2. CCKA receptor-related inhibition was associated with a membrane hyperpolarization and a decrease in input resistance that developed 2-6 min after the arrival of drug into the extracellular medium. These effects were induced by 5 nM CCK8 but not BC 264 and they were blocked by the CCKA antagonist, L-364,718, but not by the CCKB antagonist, L-365,260. 3. CCKA receptor-related inhibition was generated by a potassium current that reversed at a reversal potential E(rev) of -73 +/- 1 (mean +/- SE) mV with bathing potassium concentration [K+]o = 6 mM and at -88 +/- 1 with [K+]o = 3 mM, in agreement with the Nernst equation for potassium ions. 4. CCKB receptor-related excitation was associated with a membrane depolarization and an increase of the input resistance induced by the following agonists at threshold concentrations: CCK8 (0.2 nM) > or = BC 264 (0.4 nM) > CCK4 (10.9 nM). The increase of input resistance was abolished by L-365,260 and was maintained after blockade of the CCKA current by L-364,718. 5. CCKB receptor-related excitation, in the neurons (30% of cases) in which clear response reversal was observed, appeared to be generated by a decrease of a potassium conductance. Responses showed a reversal potential E(rev) of -68 +/- 4 mV with [K+]o = 6 mM and -89 +/- 1 mV with [K+]o = 3 mM, verifying predictions from the Nernst equation applied to potassium ions. However, in 70% of cases, clear reversal was not observed at membrane potentials negative to the theoretical potassium equilibrium potential EK. 6. In voltage clamp studies, CCK8 induced a 181 +/- 17 pA inward current associated with a 26 +/- 4% decrease in the instantaneous current (I(ins)) generated by hyperpolarizing voltage steps. This effect on I(ins) was demonstrated in the absence of effects on the outward noninactivating potassium current (IM) and on the inward noninactivating cationic current (IQ). 7. CCKB receptor-mediated excitation was not suppressed by cobalt, a blocker of calcium currents, and was not associated with a change of the calcium-dependent potassium current (IK(Ca)).(ABSTRACT TRUNCATED AT 400 WORDS)
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Chen, Long, Joseph D. Bohanick, Makoto Nishihara, Jeremy K. Seamans, and Charles R. Yang. "Dopamine D1/5 Receptor-Mediated Long-Term Potentiation of Intrinsic Excitability in Rat Prefrontal Cortical Neurons: Ca2+-Dependent Intracellular Signaling." Journal of Neurophysiology 97, no. 3 (March 2007): 2448–64. http://dx.doi.org/10.1152/jn.00317.2006.
Full textAbstract:
Prefrontal cortex (PFC) dopamine D1/5 receptors modulate long- and short-term neuronal plasticity that may contribute to cognitive functions. Synergistic to synaptic strength modulation, direct postsynaptic D1/5 receptor activation also modulates voltage-dependent ionic currents that regulate spike firing, thus altering the neuronal input–output relationships in a process called long-term potentiation of intrinsic excitability (LTP-IE). Here, the intracellular signals that mediate this D1/5 receptor-dependent LTP-IE were determined using whole cell current-clamp recordings in layer V/VI rat pyramidal neurons from PFC slices. After blockade of all major amino acid receptors ( Vhold = −65 mV) brief tetanic stimulation (20 Hz) of local afferents or application of the D1 agonist SKF81297 (0.2–50 μM) induced LTP-IE, as shown by a prolonged (>40 min) increase in depolarizing pulse-evoked spike firing. Pretreatment with the D1/5 antagonist SCH23390 (1 μM) blocked both the tetani- and D1/5 agonist-induced LTP-IE, suggesting a D1/5 receptor-mediated mechanism. The SKF81297 -induced LTP-IE was significantly attenuated by Cd2+, [Ca2+]i chelation, by inhibition of phospholipase C, protein kinase-C, and Ca2+/calmodulin kinase-II, but not by inhibition of adenylate cyclase, protein kinase-A, MAP kinase, or L-type Ca2+ channels. Thus this form of D1/5 receptor-mediated LTP-IE relied on Ca2+ influx via non-L-type Ca2+ channels, activation of PLC, intracellular Ca2+ elevation, activation of Ca2+-dependent CaMKII, and PKC to mediate modulation of voltage-dependent ion channel(s). This D1/5 receptor-mediated modulation by PKC coexists with the previously described PKA-dependent modulation of K+ and Ca2+ currents to dynamically regulate overall excitability of PFC neurons.
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Ries, Craig R., and Ernest Puil. "Mechanism of Anesthesia Revealed by Shunting Actions of Isoflurane on Thalamocortical Neurons." Journal of Neurophysiology 81, no. 4 (April 1, 1999): 1795–801. http://dx.doi.org/10.1152/jn.1999.81.4.1795.
Full textAbstract:
Mechanism of anesthesia revealed by shunting actions of isoflurane on thalamocortical neurons. By using thalamic brain slices from juvenile rats and the whole cell recording technique, we determined the effects of aqueous applications of the anesthetic isoflurane (IFL) on tonic and burst firing activities of ventrobasal relay neurons. At concentrations equivalent to those used for in vivo anesthesia, IFL induced a hyperpolarization and increased membrane conductance in a reversible and concentration-dependent manner (ionic mechanism detailed in companion paper). The increased conductance short-circuited the effectiveness of depolarizing pulses and was the main cause for inhibition of tonic firing of action potentials. Despite the IFL-induced hyperpolarization, which theoretically should have promoted bursting, the shunt blocked the low-threshold Ca2+ spike (LTS) and associated burst firing of action potentials as well as the high-threshold Ca2+ spike (HTS). Increasing the amplitude of either the depolarizing test pulse or hyperpolarizing prepulse or increasing the duration of the hyperpolarizing prepulse partially reversed the blockade of the LTS burst. In voltage-clamp experiments on the T-type Ca2+ current, which produces the LTS, IFL decreased the spatial distribution of imposed voltages and hence impaired the activation of spatially distant T channels. Although IFL may have increased a dendritic leak conductance or decreased dendritic Ca2+ currents, the somatic shunt appeared to block initiation of the LTS and HTS as well as their electrotonic propogation to the axon hillock. In summary, IFL hyperpolarized thalamocortical neurons and shunted voltage-dependent Na+ and Ca2+ currents. Considering the importance of the thalamus in relaying different sensory modalities (i.e., somatosensation, audition, and vision) and motor information as well as the corticothalamocortical loops in mediating consciousness, the shunted firing activities of thalamocortical neurons would be instrumental for the production of anesthesia in vivo.
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Nordin, C. "Computer model of membrane current and intracellular Ca2+ flux in the isolated guinea pig ventricular myocyte." American Journal of Physiology-Heart and Circulatory Physiology 265, no. 6 (December 1, 1993): H2117—H2136. http://dx.doi.org/10.1152/ajpheart.1993.265.6.h2117.
Full textAbstract:
This paper presents the equations and responses of a mathematical model that simulates the transmembrane current and intracellular concentrations of Ca2+ ([Ca2+]), Na+ ([Na+]), and K+ ([K+]) of an isolated guinea pig myocyte. The structure of the model is closely related to the formulation of DiFrancesco and Noble (9). Quantitative values are based on a large number of experimental constraints, taken from the literature on isolated myocytes as well as our own experimental studies, that describe the properties of individual channels and integrated responses of whole cells under a variety of conditions. The model was constructed as a homeostatic system. The equilibrium of the model corresponds to the resting potential and intracellular ionic concentrations of unstimulated myocytes. The model generates deviations from equilibrium corresponding to the behavior of cells after stimulation of action potentials at different rates, blockade of Na-K-adenosinetriphosphatase (ATPase), reduction in extracellular [K+], and injection of constant depolarizing current. Simulations from the model suggest that changes in myoplasmic [Ca2+] at different stimulation rates, the generation of restitution and postextrasystolic potentiation, and the development of intracellular [Ca2+] oscillations arise simply from different interactions between uptake of Ca2+ into the sarcoplasmic reticulum via the Ca(2+)-ATPase, Ca(2+)-induced Ca2+ release of Ca2+ into the myoplasm, flux between regions of uptake and release, and leakage between sarcoplasmic reticulum and myoplasm. The model also demonstrates that a wide variety of basic electrophysiological responses of the isolated guinea pig myocyte can be simulated with quantitative precision by a single set of equations based on experimentally measured transmembrane current and intracellular [Ca2+] and [Na+].
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Stafstrom, C. E., P. C. Schwindt, M. C. Chubb, and W. E. Crill. "Properties of persistent sodium conductance and calcium conductance of layer V neurons from cat sensorimotor cortex in vitro." Journal of Neurophysiology 53, no. 1 (January 1, 1985): 153–70. http://dx.doi.org/10.1152/jn.1985.53.1.153.
Full textAbstract:
Properties of the persistent sodium conductance and the calcium conductance of layer V neurons from cat sensorimotor cortex were examined in an in vitro slice preparation by use of a single microelectrode, somatic voltage clamp, current clamp, intra- and extracellular application of blocking agents, and extracellular ion substitution. The persistent sodium current (INaP) attained its steady level within 2-4 ms of a step change in voltage at every potential where it could be examined directly [to about 40 mV positive to resting potential (RP)]. Because of its fast onset INaP can be activated during a single excitatory postsynaptic potential (EPSP) and can influence the subsequent voltage time course and cell excitability. Application of a depolarizing holding potential greater than or equal to 20 mV positive to RP could inactivate spikes, thus allowing examination of INaP at voltages positive to spike threshold. At every potential where INaP was visible, it was mixed with a slow outward current. After depressing potassium currents with blocking agents, INaP could be observed during depolarizations to about 40 mV positive to RP where it is normally hidden by the larger outward currents. Indirect evidence suggests that INaP is present and large during prolonged depolarizations greater than 50 mV positive to RP. INaP was blocked by intracellular injection of the lidocaine derivative QX-314, as well as by extracellular tetrodotoxin (TTX). INaP was much more sensitive to QX-314 than was the height and rate of rise of the spike. This observation and the results in paragraph 3 above are best explained by separate INaP and spike sodium channels. After blockade of INaP and sodium spikes, Ca2+ spikes could be evoked only if potassium currents were first depressed. The Ca2+-dependent nature of the regenerative potentials was indicated by their disappearance when Co2+ or Mn2+ was substituted for Ca2+ in the perfusate and by the appearance of greatly enhanced potentials of similar form when Ba2+ was substituted for Ca2+. Ba2+ substitution greatly enhanced evoked and spontaneous synaptic potentials. Prolonged-plateau action potentials could be evoked in the presence of TTX and Ba2+. Ca2+ spike threshold was 30-40 mV positive to RP, which is significantly more positive than sodium spike threshold. Results of voltage clamp in the normal perfusate and in the presence of Ca2+-blockers or Ba2+ indicated that little or no Ca2+ conductance is activated in the voltage range 25 mV positive to RP where INaP is the dominant ionic current.(ABSTRACT TRUNCATED AT 400 WORDS)
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Figueroa, Xavier F., Chien-Chang Chen, Kevin P. Campbell, David N. Damon, Kathleen H. Day, Susan Ramos, and Brian R. Duling. "Are voltage-dependent ion channels involved in the endothelial cell control of vasomotor tone?" American Journal of Physiology-Heart and Circulatory Physiology 293, no. 3 (September 2007): H1371—H1383. http://dx.doi.org/10.1152/ajpheart.01368.2006.
Full textAbstract:
In the microcirculation, longitudinal conduction of vasomotor responses provides an essential means of coordinating flow distribution among vessels in a complex network. Spread of current along the vessel axis can display a regenerative component, which leads to propagation of vasomotor signals over many millimeters; the ionic basis for the regenerative response is unknown. We examined the responses to 10 s of focal electrical stimulation (30 Hz, 2 ms, 30 V) of mouse cremaster arterioles to test the hypothesis that voltage-dependent Na+ (Nav) and Ca2+ channels might be activated in long-distance signaling in microvessels. Electrical stimulation evoked a vasoconstriction at the site of stimulation and a spreading, nondecremental conducted dilation. Endothelial damage (air bubble) blocked conduction of the vasodilation, indicating an involvement of the endothelium. The Nav channel blocker bupivacaine also blocked conduction, and TTX attenuated it. The Nav channel activator veratridine induced an endothelium-dependent dilation. The Nav channel isoforms Nav1.2, Nav1.6, and Nav1.9 were detected in the endothelial cells of cremaster arterioles by immunocytochemistry. These findings are consistent with the involvement of Nav channels in the conducted response. BAPTA buffering of endothelial cell Ca2+ delayed and reduced the conducted dilation, which was almost eliminated by Ni2+, amiloride, or deletion of α1H T-type Ca2+ (Cav3.2) channels. Blockade of endothelial nitric oxide synthase or Ca2+-activated K+ channels also inhibited the conducted vasodilation. Our findings indicate that an electrically induced signal can propagate along the vessel axis via the endothelium and can induce sequential activation of Nav and Cav3.2 channels. The resultant Ca2+ influx activates endothelial nitric oxide synthase and Ca2+-activated K+ channels, triggering vasodilation.