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Journal articles on the topic 'Tandem Pore Domain Potassium Channels'

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Published: 4 June 2021

Last updated: 11 February 2022

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1

Kindler, Christoph H., Spencer C. Yost, and Andrew T. Gray. "Local Anesthetic Inhibition of Baseline Potassium Channels with Two Pore Domains in Tandem." Anesthesiology 90, no. 4 (April 1, 1999): 1092–102. http://dx.doi.org/10.1097/00000542-199904000-00024.

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Background Recently, a new structural family of potassium channels characterized by two pore domains in tandem within their primary amino acid sequence was identified. These tandem pore domain potassium channels are not gated by voltage and appear to be involved in the control of baseline membrane conductances. The goal of this study was to identify mechanisms of local anesthetic action on these channels. Methods Oocytes of Xenopus laevis were injected with cRNA from five cloned tandem pore domain baseline potassium channels (TASK, TREK-1, TOK1, ORK1, and TWIK-1), and the effects of several local anesthetics on the heterologously expressed channels were assayed using two-electrode voltage-clamp and current-clamp techniques. Results Bupivacaine (1 mM) inhibited all studied tandem pore potassium channels, with TASK inhibited most potently. The potency of inhibition was directly correlated with the octanol: buffer distribution coefficient of the local anesthetic, with the exception of tetracaine, to which TASK is relatively insensitive. The approximate 50% inhibitory concentrations of TASK were 709 microM mepivacaine, 222 microM lidocaine, 51 microM R(+)-ropivacaine, 53 microM S(-)-ropivacaine, 668 microM tetracaine, 41 microM bupivacaine, and 39 microM etidocaine. Local anesthetics (1 mM) significantly depolarized the resting membrane potential of TASK cRNA-injected oocytes compared with saline-injected control oocytes (tetracaine 22+/-6 mV rs. 7+/-1 mV, respectively, and bupivacaine 31+/-7 mV vs. 6+/-4 mV). Conclusions Local anesthetics inhibit tandem pore domain baseline potassium channels, and they could depolarize the resting membrane potential of cells expressing these channels. Whether inhibition of these channels contributes to conduction blockade or to the adverse effects of local anesthetics remains to be determined.

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2

Gray, Andrew T., Byron B. Zhao, Christoph H. Kindler, Bruce D. Winegar, Matthew J. Mazurek, Jie Xu, Raymond A. Chavez, John R. Forsayeth, and C. Spencer Yost. "Volatile Anesthetics Activate the Human Tandem Pore Domain Baseline K+Channel KCNK5." Anesthesiology 92, no. 6 (June 1, 2000): 1722–30. http://dx.doi.org/10.1097/00000542-200006000-00032.

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Background Previous studies have identified a volatile anesthetic-induced increase in baseline potassium permeability and concomitant neuronal inhibition. The emerging family of tandem pore domain potassium channels seems to function as baseline potassium channels in vivo. Therefore, we studied the effects of clinically used volatile anesthetics on a recently described member of this family. Methods A cDNA clone containing the coding sequence of KCNK5 was isolated from a human brain library. Expression of KCNK5 in the central nervous system was determined by Northern blot analysis and reverse-transcription polymerase chain reaction. Functional expression of the channel was achieved by injection of cRNA into Xenopus laevis oocytes. Results Expression of KCNK5 was detected in cerebral cortex, medulla, and spinal cord. When heterologously expressed in Xenopus oocytes, KCNK5 currents exhibited delayed activation, outward rectification, proton sensitivity, and modulation by protein kinase C. Clinical concentrations of volatile general anesthetics potentiated KCNK5 currents by 8-30%. Conclusion Human KCNK5 is a tandem pore domain potassium channel exhibiting delayed activation and sensitivity to volatile anesthetics and may therefore have a role in suppressing cellular excitability during general anesthesia.

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Bryan, Robert M., Junping You, Sharon C. Phillips, Jon J. Andresen, Eric E. Lloyd, Paul A. Rogers, Stuart E. Dryer, and Sean P. Marrelli. "Evidence for two-pore domain potassium channels in rat cerebral arteries." American Journal of Physiology-Heart and Circulatory Physiology 291, no. 2 (August 2006): H770—H780. http://dx.doi.org/10.1152/ajpheart.01377.2005.

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Little is known about the presence and function of two-pore domain K+ (K2P) channels in vascular smooth muscle cells (VSMCs). Five members of the K2P channel family are known to be directly activated by arachidonic acid (AA). The purpose of this study was to determine 1) whether AA-sensitive K2P channels are expressed in cerebral VSMCs and 2) whether AA dilates the rat middle cerebral artery (MCA) by increasing K+ currents in VSMCs via an atypical K+ channel. RT-PCR revealed message for the following AA-sensitive K2P channels in rat MCA: tandem of P domains in weak inward rectifier K+ (TWIK-2), TWIK-related K+ (TREK-1 and TREK-2), TWIK-related AA-stimulated K+ (TRAAK), and TWIK-related halothane-inhibited K+ (THIK-1) channels. However, in isolated VSMCs, only message for TWIK-2 was found. Western blotting showed that TWIK-2 is present in MCA, and immunohistochemistry further demonstrated its presence in VSMCs. AA (10–100 μM) dilated MCAs through an endothelium-independent mechanism. AA-induced dilation was not affected by inhibition of cyclooxygenase, epoxygenase, or lipoxygenase or inhibition of classical K+ channels with 10 mM TEA, 3 mM 4-aminopyridine, 10 μM glibenclamide, or 100 μM Ba2+. AA-induced dilations were blocked by 50 mM K+, indicating involvement of a K+ channel. AA (10 μM) increased whole cell K+ currents in dispersed cerebral VSMCs. AA-induced currents were not affected by inhibitors of the AA metabolic pathways or blockade of classical K+ channels. We conclude that AA dilates the rat MCA and increases K+ currents in VSMCs via an atypical K+ channel that is likely a member of the K2P channel family.

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4

Lengyel, Miklós, Gábor Czirják, David A. Jacobson, and Péter Enyedi. "TRESK and TREK-2 two-pore-domain potassium channel subunits form functional heterodimers in primary somatosensory neurons." Journal of Biological Chemistry 295, no. 35 (July 7, 2020): 12408–25. http://dx.doi.org/10.1074/jbc.ra120.014125.

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Two-pore-domain potassium channels (K2P) are the major determinants of the background potassium conductance. They play a crucial role in setting the resting membrane potential and regulating cellular excitability. These channels form homodimers; however, a few examples of heterodimerization have also been reported. The K2P channel subunits TRESK and TREK-2 provide the predominant background potassium current in the primary sensory neurons of the dorsal root and trigeminal ganglia. A recent study has shown that a TRESK mutation causes migraine because it leads to the formation of a dominant negative truncated TRESK fragment. Surprisingly, this fragment can also interact with TREK-2. In this study, we determined the biophysical and pharmacological properties of the TRESK/TREK-2 heterodimer using a covalently linked TRESK/TREK-2 construct to ensure the assembly of the different subunits. The tandem channel has an intermediate single-channel conductance compared with the TRESK and TREK-2 homodimers. Similar conductance values were recorded when TRESK and TREK-2 were coexpressed, demonstrating that the two subunits can spontaneously form functional heterodimers. The TRESK component confers calcineurin-dependent regulation to the heterodimer and gives rise to a pharmacological profile similar to the TRESK homodimer, whereas the presence of the TREK-2 subunit renders the channel sensitive to the selective TREK-2 activator T2A3. In trigeminal primary sensory neurons, we detected single-channel activity with biophysical and pharmacological properties similar to the TRESK/TREK-2 tandem, indicating that WT TRESK and TREK-2 subunits coassemble to form functional heterodimeric channels also in native cells.

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5

Smith, Howard. "Calcineurin as a Nociceptor Modulator." Pain Physician 4;12, no. 4;7 (July 14, 2009): E309—E318. http://dx.doi.org/10.36076/ppj.2009/12/e09.

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Calcineurin may be involved in affecting nociceptive processes in multiple circumstances. It is conceivable that interfering with calcineurin’s normal role in contributing to glial resting membrane potential, via its effects on the ion channel (TRESK) [tandem-pore-domain weakly inward rectifying potassium channels (TWIK)-related spinal cord potassium channels] may facilitate nociception. Another aspect of calcineurin function may be its role in the pronociceptive signaling of nuclear factor of activated T-cells (NFAT). NFAT activation via mediators (e.g. Substance P, brain-derived neurotrophic factor, nerve growth factor, bradykinin) appears to be dependent on calcineurin function. This calcineurin-regulated NFAT signaling may subsequently lead to transcription of pronociceptive genes as well as upregulation of pronociceptive chemokine receptors in the dorsal root ganglion. In fact, multiple articles have described the clinical use of calcineurin-inhibitors leading to pain, a phenomenon referred to as calcineurin inhibitor-induced pain syndrome (CIPS). Thus, it appears that calcineurin functions may encompass actions which promote or dampen nociceptive processes. A greater understanding of the physiology of calcineurin, especially as it relates to modulating nociception may lead to the development of novel analgesic targets in attempts to optimally alleviate patient discomfort. Key words: Pain, neuropathic, calcineurin, NFAT, TRESK-[Tandem-pore-domain weakly inward rectifying potassium channels (TWIK)-related spinal cord potassium channels], CIPS (calcineurin-induced pain syndrome)

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Noto, Federico, Sandra Recuero, Julián Valencia, Beatrice Saporito, Domenico Robbe, Sergi Bonet, Augusto Carluccio, and Marc Yeste. "Inhibition of Potassium Channels Affects the Ability of Pig Spermatozoa to Elicit Capacitation and Trigger the Acrosome Exocytosis Induced by Progesterone." International Journal of Molecular Sciences 22, no. 4 (February 17, 2021): 1992. http://dx.doi.org/10.3390/ijms22041992.

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During capacitation, sperm undergo a myriad of changes, including remodeling of plasma membrane, modification of sperm motility and kinematic parameters, membrane hyperpolarization, increase in intracellular calcium levels, and tyrosine phosphorylation of certain sperm proteins. While potassium channels have been reported to be crucial for capacitation of mouse and human sperm, their role in pigs has not been investigated. With this purpose, sperm samples from 15 boars were incubated in capacitation medium for 300 min with quinine, a general blocker of potassium channels (including voltage-gated potassium channels, calcium-activated potassium channels, and tandem pore domain potassium channels), and paxilline (PAX), a specific inhibitor of calcium-activated potassium channels. In all samples, acrosome exocytosis was induced after 240 min of incubation with progesterone. Plasma membrane and acrosome integrity, membrane lipid disorder, intracellular calcium levels, mitochondrial membrane potential, and total and progressive sperm motility were evaluated after 0, 120, and 240 min of incubation, and after 5, 30, and 60 min of progesterone addition. Although blocking potassium channels with quinine and PAX prevented sperm to elicit in vitro capacitation by impairing motility and mitochondrial function, as well as reducing intracellular calcium levels, the extent of that inhibition was larger with quinine than with PAX. Therefore, while our data support that calcium-activated potassium channels are essential for sperm capacitation in pigs, they also suggest that other potassium channels, such as the voltage-gated, tandem pore domain, and mitochondrial ATP-regulated ones, are involved in that process. Thus, further research is needed to elucidate the specific functions of these channels and the mechanisms underlying its regulation during sperm capacitation.

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Skatchkov, S. N., M. J. Eaton, Y. M. Shuba, Y. V. Kucheryavykh, C. Derst, R. W. Veh, A. Wurm, et al. "Tandem-pore domain potassium channels are functionally expressed in retinal (Müller) glial cells." Glia 53, no. 3 (2005): 266–76. http://dx.doi.org/10.1002/glia.20280.

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8

Blin, Sandy, Ismail Ben Soussia, Eun-Jin Kim, Frédéric Brau, Dawon Kang, Florian Lesage, and Delphine Bichet. "Mixing and matching TREK/TRAAK subunits generate heterodimeric K2P channels with unique properties." Proceedings of the National Academy of Sciences 113, no. 15 (March 28, 2016): 4200–4205. http://dx.doi.org/10.1073/pnas.1522748113.

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The tandem of pore domain in a weak inwardly rectifying K+ channel (Twik)-related acid-arachidonic activated K+ channel (TRAAK) and Twik-related K+ channels (TREK) 1 and TREK2 are active as homodimers gated by stretch, fatty acids, pH, and G protein-coupled receptors. These two-pore domain potassium (K2P) channels are broadly expressed in the nervous system where they control excitability. TREK/TRAAK KO mice display altered phenotypes related to nociception, neuroprotection afforded by polyunsaturated fatty acids, learning and memory, mood control, and sensitivity to general anesthetics. These channels have emerged as promising targets for the development of new classes of anesthetics, analgesics, antidepressants, neuroprotective agents, and drugs against addiction. Here, we show that the TREK1, TREK2, and TRAAK subunits assemble and form active heterodimeric channels with electrophysiological, regulatory, and pharmacological properties different from those of homodimeric channels. Heteromerization occurs between all TREK variants produced by alternative splicing and alternative translation initiation. These results unveil a previously unexpected diversity of K2P channels that will be challenging to analyze in vivo, but which opens new perspectives for the development of clinically relevant drugs.

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Rivas-Ramírez, Paula, Antonio Reboreda, Lola Rueda-Ruzafa, Salvador Herrera-Pérez, and J. Antonio Lamas. "PIP2 Mediated Inhibition of TREK Potassium Currents by Bradykinin in Mouse Sympathetic Neurons." International Journal of Molecular Sciences 21, no. 2 (January 8, 2020): 389. http://dx.doi.org/10.3390/ijms21020389.

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Bradykinin (BK), a hormone inducing pain and inflammation, is known to inhibit potassium M-currents (IM) and to increase the excitability of the superior cervical ganglion (SCG) neurons by activating the Ca2+-calmodulin pathway. M-current is also reduced by muscarinic agonists through the depletion of membrane phosphatidylinositol 4,5-biphosphate (PIP2). Similarly, the activation of muscarinic receptors inhibits the current through two-pore domain potassium channels (K2P) of the “Tandem of pore-domains in a Weakly Inward rectifying K+ channel (TWIK)-related channels” (TREK) subfamily by reducing PIP2 in mouse SCG neurons (mSCG). The aim of this work was to test and characterize the modulation of TREK channels by bradykinin. We used the perforated-patch technique to investigate riluzole (RIL) activated currents in voltage- and current-clamp experiments. RIL is a drug used in the palliative treatment of amyotrophic lateral sclerosis and, in addition to blocking voltage-dependent sodium channels, it also selectively activates the K2P channels of the TREK subfamily. A cell-attached patch-clamp was also used to investigate TREK-2 single channel currents. We report here that BK reduces spike frequency adaptation (SFA), inhibits the riluzole-activated current (IRIL), which flows mainly through TREK-2 channels, by about 45%, and reduces the open probability of identified single TREK-2 channels in cultured mSCG cells. The effect of BK on IRIL was precluded by the bradykinin receptor (B2R) antagonist HOE-140 (d-Arg-[Hyp3, Thi5, d-Tic7, Oic8]BK) but also by diC8PIP2 which prevents PIP2 depletion when phospholipase C (PLC) is activated. On the contrary, antagonizing inositol triphosphate receptors (IP3R) using 2-aminoethoxydiphenylborane (2-APB) or inhibiting protein kinase C (PKC) with bisindolylmaleimide did not affect the inhibition of IRIL by BK. In conclusion, bradykinin inhibits TREK-2 channels through the activation of B2Rs resulting in PIP2 depletion, much like we have demonstrated for muscarinic agonists. This mechanism implies that TREK channels must be relevant for the capture of information about pain and visceral inflammation.

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10

Li, Zheng-Bin, Hai-Xia Zhang, Liao-Liao Li, and Xiao-Liang Wang. "Enhanced expressions of arachidonic acid-sensitive tandem-pore domain potassium channels in rat experimental acute cerebral ischemia." Biochemical and Biophysical Research Communications 327, no. 4 (February 2005): 1163–69. http://dx.doi.org/10.1016/j.bbrc.2004.12.124.

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11

Ravens, Ursula. "Atrial-selective K+ channel blockers: potential antiarrhythmic drugs in atrial fibrillation?" Canadian Journal of Physiology and Pharmacology 95, no. 11 (November 2017): 1313–18. http://dx.doi.org/10.1139/cjpp-2017-0024.

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In the wake of demographic change in Western countries, atrial fibrillation has reached an epidemiological scale, yet current strategies for drug treatment of the arrhythmia lack sufficient efficacy and safety. In search of novel medications, atrial-selective drugs that specifically target atrial over other cardiac functions have been developed. Here, I will address drugs acting on potassium (K+) channels that are either predominantly expressed in atria or possess electrophysiological properties distinct in atria from ventricles. These channels include the ultra-rapidly activating, delayed outward-rectifying Kv1.5 channel conducting IKur, the acetylcholine-activated inward-rectifying Kir3.1/Kir3.4 channel conducting IK,ACh, the Ca2+-activated K+ channels of small conductance (SK) conducting ISK, and the two-pore domain K+ (K2P) channels (tandem of P domains, weak inward-rectifying K+ channels (TWIK-1), TWIK-related acid-sensitive K+ channels (TASK-1 and TASK-3)) that are responsible for voltage-independent background currents ITWIK-1, ITASK-1, and ITASK-3. Direct drug effects on these channels are described and their putative value in treatment of atrial fibrillation is discussed. Although many potential drug targets have emerged in the process of unravelling details of the pathophysiological mechanisms responsible for atrial fibrillation, we do not know whether novel antiarrhythmic drugs will be more successful when modulating many targets or a single specific one. The answer to this riddle can only be solved in a clinical context.

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Ji, Xin-cai, Wan-hong Zhao, Dong-xu Cao, Qiao-qiao Shi, and Xiao-liang Wang. "Novel neuroprotectant chiral 3-n-butylphthalide inhibits tandem-pore-domain potassium channel TREK-1." Acta Pharmacologica Sinica 32, no. 2 (February 2011): 182–87. http://dx.doi.org/10.1038/aps.2010.210.

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13

Magra, Merzesh, Steven Hughes, Alicia J. El Haj, and Nicola Maffulli. "VOCCs and TREK-1 ion channel expression in human tenocytes." American Journal of Physiology-Cell Physiology 292, no. 3 (March 2007): C1053—C1060. http://dx.doi.org/10.1152/ajpcell.00053.2006.

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Mechanosensitive and voltage-gated ion channels are known to perform important roles in mechanotransduction in a number of connective tissues, including bone and muscle. It is hypothesized that voltage-gated and mechanosensitive ion channels also may play a key role in some or all initial responses of human tenocytes to mechanical stimulation. However, to date there has been no direct investigation of ion channel expression by human tenocytes. Human tenocytes were cultured from patellar tendon samples harvested from five patients undergoing routine total knee replacement surgery (mean age: 66 yr; range: 63–73 yr). RT-PCR, Western blotting, and whole cell electrophysiological studies were performed to investigate the expression of different classes of ion channels within tenocytes. Human tenocytes expressed mRNA and protein encoding voltage-operated calcium channel (VOCC) subunits (Ca α1A, Ca α1C, Ca α1D, Ca α2δ1) and the mechanosensitive tandem pore domain potassium channel (2PK+) TREK-1. They exhibit whole cell currents consistent with the functional expression of these channels. In addition, other ionic currents were detected within tenocytes consistent with the expression of a diverse array of other ion channels. VOCCs and TREK channels have been implicated in mechanotransduction signaling pathways in numerous connective tissue cell types. These mechanisms may be present in human tenocytes. In addition, human tenocytes may express other channel currents. Ion channels may represent potential targets for the pharmacological management of chronic tendinopathies.

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14

Chavez, Raymond A., Andrew T. Gray, Byron B. Zhao, Christoph H. Kindler, Matthew J. Mazurek, Yash Mehta, John R. Forsayeth, and C. Spencer Yost. "TWIK-2, a new weak inward rectifying member of the tandem pore domain potassium channel family." Journal of Biological Chemistry 274, no. 34 (August 1999): 24440. http://dx.doi.org/10.1016/s0021-9258(19)55579-x.

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15

Chavez, Raymond A., Andrew T. Gray, Byron B. Zhao, Christoph H. Kindler, Matthew J. Mazurek, Yash Mehta, John R. Forsayeth, and C. Spencer Yost. "TWIK-2, a New Weak Inward Rectifying Member of the Tandem Pore Domain Potassium Channel Family." Journal of Biological Chemistry 274, no. 12 (March 19, 1999): 7887–92. http://dx.doi.org/10.1074/jbc.274.12.7887.

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16

Gray, Andrew T., Bruce D. Winegar, Dmitri J. Leonoudakis, John R. Forsayeth, and Spencer C. Yost. "TOK1 Is a Volatile Anesthetic Stimulated K+Channel." Anesthesiology 88, no. 4 (April 1, 1998): 1076–84. http://dx.doi.org/10.1097/00000542-199804000-00029.

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Background Volatile anesthetic agents can activate the S channel, a baseline potassium (K+) channel, of the marine mollusk Aplysia. To investigate whether cloned ion channels with electrophysiologic properties similar to the S channel (potassium selectivity, outward rectification, and activation independent of voltage) also are modulated by volatile anesthetic agents, the authors expressed the cloned yeast ion channel TOK1 (tandem pore domain, outwardly rectifying K+ channel) in Xenopus oocytes and studied its sensitivity to volatile agents. Methods Standard two-electrode voltage and patch clamp recording methods were used to study TOK1 channels expressed in Xenopus oocytes. Results Studies with two-electrode voltage clamp at room temperature showed that halothane, isoflurane, and desflurane increased TOK1 outward currents by 48-65% in barium Frog Ringer's perfusate. The concentrations at which 50% potentiation occurred (EC50 values) were in the range of 768-814 microM (0.016-0.044 atm) and had a rank order of potency in atm in which halothane > isoflurane > desflurane. The potentiation of TOK1 by volatile anesthetic agents was rapid and reversible (onset and offset, 1-20 s). In contrast, the nonanesthetic 1,2-dichlorohexafluorocyclobutane did not potentiate TOK1 currents in concentrations up to five times the MAC value predicted by the Meyer-Overton hypothesis based on oil/gas partition coefficients. Single TOK1 channel currents were recorded from excised outside-out patches. The single channel open probability increased as much as twofold in the presence of isoflurane and rapidly returned to the baseline values on washout. Volatile anesthetic agents did not alter the TOK1 single channel current-voltage (I-V) relationship, however, suggesting that the site of action does not affect the permeation pathway of the channel. Conclusion TOK1 is a potassium channel that is stimulated by volatile anesthetic agents. The concentrations over which potentiation occurred (EC50 values) were higher than those commonly used in clinical practice (approximately twice MAC).

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Lee, Sang-Yeon, Hyun Been Choi, Mina Park, Il Soon Choi, Jieun An, Ami Kim, Eunku Kim, et al. "Novel KCNQ4 variants in different functional domains confer genotype- and mechanism-based therapeutics in patients with nonsyndromic hearing loss." Experimental & Molecular Medicine 53, no. 7 (July 2021): 1192–204. http://dx.doi.org/10.1038/s12276-021-00653-4.

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AbstractLoss-of-function variant in the gene encoding the KCNQ4 potassium channel causes autosomal dominant nonsyndromic hearing loss (DFNA2), and no effective pharmacotherapeutics have been developed to reverse channel activity impairment. Phosphatidylinositol 4,5-bisphosphate (PIP2), an obligatory phospholipid for maintaining KCNQ channel activity, confers differential pharmacological sensitivity of channels to KCNQ openers. Through whole-exome sequencing of DFNA2 families, we identified three novel KCNQ4 variants related to diverse auditory phenotypes in the proximal C-terminus (p.Arg331Gln), the C-terminus of the S6 segment (p.Gly319Asp), and the pore region (p.Ala271_Asp272del). Potassium currents in HEK293T cells expressing each KCNQ4 variant were recorded by patch-clamp, and functional recovery by PIP2 expression or KCNQ openers was examined. In the homomeric expression setting, the three novel KCNQ4 mutant proteins lost conductance and were unresponsive to KCNQ openers or PIP2 expression. Loss of p.Arg331Gln conductance was slightly restored by a tandem concatemer channel (WT-p.R331Q), and increased PIP2 expression further increased the concatemer current to the level of the WT channel. Strikingly, an impaired homomeric p.Gly319Asp channel exhibited hyperactivity when a concatemer (WT-p.G319D), with a negative shift in the voltage dependence of activation. Correspondingly, a KCNQ inhibitor and chelation of PIP2 effectively downregulated the hyperactive WT-p.G319D concatemer channel. Conversely, the pore-region variant (p.Ala271_Asp272del) was nonrescuable under any condition. Collectively, these novel KCNQ4 variants may constitute therapeutic targets that can be manipulated by the PIP2 level and KCNQ-regulating drugs under the physiological context of heterozygous expression. Our research contributes to the establishment of a genotype/mechanism-based therapeutic portfolio for DFNA2.

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Bertaccini, Edward J., Robert Dickinson, James R. Trudell, and Nicholas P. Franks. "Molecular Modeling of a Tandem Two Pore Domain Potassium Channel Reveals a Putative Binding Site for General Anesthetics." ACS Chemical Neuroscience 5, no. 12 (October 31, 2014): 1246–52. http://dx.doi.org/10.1021/cn500172e.

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Wells, G. D., Q. Y. Tang, R. Heler, G. J. Tompkins-MacDonald, E. N. Pritchard, S. P. Leys, D. E. Logothetis, and L. M. Boland. "A unique alkaline pH-regulated and fatty acid-activated tandem pore domain potassium channel (K2P) from a marine sponge." Journal of Experimental Biology 215, no. 14 (June 20, 2012): 2435–44. http://dx.doi.org/10.1242/jeb.066233.

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Nishizuka, Makoto, Takahiro Hayashi, Mami Asano, Shigehiro Osada, and Masayoshi Imagawa. "KCNK10, a Tandem Pore Domain Potassium Channel, Is a Regulator of Mitotic Clonal Expansion during the Early Stage of Adipocyte Differentiation." International Journal of Molecular Sciences 15, no. 12 (December 9, 2014): 22743–56. http://dx.doi.org/10.3390/ijms151222743.

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Braun, Andrew P. "Two-pore domain potassium channels." Channels 6, no. 3 (May 2012): 139–40. http://dx.doi.org/10.4161/chan.20973.

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Kindler, Christoph H., and Spencer C. Yost. "Two-Pore Domain Potassium Channels." Regional Anesthesia and Pain Medicine 30, no. 3 (May 2005): 261–74. http://dx.doi.org/10.1097/00115550-200505000-00009.

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Mathie, Alistair, and Brian Robertson. "MAMMALIAN TWO-PORE DOMAIN POTASSIUM CHANNELS." Physiology News, Summer 2001 (July 1, 2001): 5–8. http://dx.doi.org/10.36866/pn.43.5.

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Ryoo, Kanghyun, and Jae-Yong Park. "Two-pore Domain Potassium Channels in Astrocytes." Experimental Neurobiology 25, no. 5 (October 31, 2016): 222–32. http://dx.doi.org/10.5607/en.2016.25.5.222.

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Lamas, JAntonio, and Diego Fernández-Fernández. "Tandem pore TWIK-related potassium channels and neuroprotection." Neural Regeneration Research 14, no. 8 (2019): 1293. http://dx.doi.org/10.4103/1673-5374.253506.

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Yost, C. "Update on Tandem Pore (2P) Domain K+ Channels." Current Drug Targets 4, no. 4 (May 1, 2003): 347–51. http://dx.doi.org/10.2174/1389450033491091.

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Mathie, Alistair, Kathryn A. Rees, Mickael F. El Hachmane, and Emma L. Veale. "Trafficking of Neuronal Two Pore Domain Potassium Channels." Current Neuropharmacology 8, no. 3 (September 1, 2010): 276–86. http://dx.doi.org/10.2174/157015910792246146.

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Kim, Donghee. "Physiology and Pharmacology of Two-Pore Domain Potassium Channels." Current Pharmaceutical Design 11, no. 21 (August 1, 2005): 2717–36. http://dx.doi.org/10.2174/1381612054546824.

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Mathie, Alistair, Ehab Al-Moubarak, and Emma L. Veale. "SYMPOSIUM REVIEW: Gating of two pore domain potassium channels." Journal of Physiology 588, no. 17 (August 31, 2010): 3149–56. http://dx.doi.org/10.1113/jphysiol.2010.192344.

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Bandulik, Sascha, Philipp Tauber, Enzo Lalli, Jacques Barhanin, and Richard Warth. "Two-pore domain potassium channels in the adrenal cortex." Pflügers Archiv - European Journal of Physiology 467, no. 5 (October 23, 2014): 1027–42. http://dx.doi.org/10.1007/s00424-014-1628-6.

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Lesage, Florian, and Michel Lazdunski. "Molecular and functional properties of two-pore-domain potassium channels." American Journal of Physiology-Renal Physiology 279, no. 5 (November 1, 2000): F793—F801. http://dx.doi.org/10.1152/ajprenal.2000.279.5.f793.

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The two-pore-domain K+ channels, or K2P channels, constitute a novel class of K+channel subunits. They have four transmembrane segments and are active as dimers. The tissue distribution of these channels is widespread, and they are found in both excitable and nonexcitable cells. K2P channels produce currents with unusual characteristics. They are quasi-instantaneous and noninactivating, and they are active at all membrane potentials and insensitive to the classic K+ channel blockers. These properties designate them as background K+ channels. They are expected to play a major role in setting the resting membrane potential in many cell types. Another salient feature of K2P channels is the diversity of their regulatory mechanisms. The weak inward rectifiers TWIK-1 and TWIK-2 are stimulated by activators of protein kinase C and decreased by internal acidification, the baseline TWIK-related acid-sensitive K+ (TASK)-1 and TASK-2 channels are sensitive to external pH changes in a narrow range near physiological pH, and the TWIK-related (TREK)-1 and TWIK-related arachidonic acid-stimulated K+ (TRAAK) channels are the first cloned polyunsaturated fatty acids-activated and mechanogated K+ channels. The recent demonstration that TASK-1 and TREK-1 channels are activated by inhalational general anesthetics, and that TRAAK is activated by the neuroprotective agent riluzole, indicates that this novel class of K+ channels is an interesting target for new therapeutic developments.

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Enyedi, Péter, Gabriella Braun, and Gábor Czirják. "TRESK: The lone ranger of two-pore domain potassium channels." Molecular and Cellular Endocrinology 353, no. 1-2 (April 2012): 75–81. http://dx.doi.org/10.1016/j.mce.2011.11.009.

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33

Budde, Thomas, Jürgen Daut, Armin Kurtz, and Hans-Christian Pape. "Two-pore-domain potassium channels: regulators of many cellular functions." Pflügers Archiv - European Journal of Physiology 467, no. 5 (March 14, 2015): 865–66. http://dx.doi.org/10.1007/s00424-015-1699-z.

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34

Ketchum, Karen A., William J. Joiner, Andrew J. Sellers, Leonard K. Kaczmarek, and Steve A. N. Goldstein. "A new family of outwardly rectifying potassium channel proteins with two pore domains in tandem." Nature 376, no. 6542 (August 1995): 690–95. http://dx.doi.org/10.1038/376690a0.

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35

Leonoudakis, Dmitri, Andrew T. Gray, Bruce D. Winegar, Christoph H. Kindler, Masato Harada, Donald M. Taylor, Raymond A. Chavez, John R. Forsayeth, and C. Spencer Yost. "An Open Rectifier Potassium Channel with Two Pore Domains in Tandem Cloned from Rat Cerebellum." Journal of Neuroscience 18, no. 3 (February 1, 1998): 868–77. http://dx.doi.org/10.1523/jneurosci.18-03-00868.1998.

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36

Richter, Trevor A., Gennady A. Dvoryanchikov, Nirupa Chaudhari, and Stephen D. Roper. "Acid-Sensitive Two-Pore Domain Potassium (K2P) Channels in Mouse Taste Buds." Journal of Neurophysiology 92, no. 3 (September 2004): 1928–36. http://dx.doi.org/10.1152/jn.00273.2004.

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Sour (acid) taste is postulated to result from intracellular acidification that modulates one or more acid-sensitive ion channels in taste receptor cells. The identity of such channel(s) remains uncertain. Potassium channels, by regulating the excitability of taste cells, are candidates for acid transducers. Several 2-pore domain potassium leak conductance channels (K2P family) are sensitive to intracellular acidification. We examined their expression in mouse vallate and foliate taste buds using RT-PCR, and detected TWIK-1 and -2, TREK-1 and -2, and TASK-1. Of these, TWIK-1 and TASK-1 were preferentially expressed in taste cells relative to surrounding nonsensory epithelium. The related TRESK channel was not detected, whereas the acid-insensitive TASK-2 was. Using confocal imaging with pH-, Ca2+-, and voltage-sensitive dyes, we tested pharmacological agents that are diagnostic for these channels. Riluzole (500 μM), selective for TREK-1 and -2 channels, enhanced acid taste responses. In contrast, halothane (≤ ∼17 mM), which acts on TREK-1 and TASK-1 channels, blocked acid taste responses. Agents diagnostic for other 2-pore domain and voltage-gated potassium channels (anandamide, 10 μM; Gd3+, 1 mM; arachidonic acid, 100 μM; quinidine, 200 μM; quinine, 100 mM; 4-AP, 10 mM; and TEA, 1 mM) did not affect acid responses. The expression of 2-pore domain channels and our pharmacological characterization suggest that a matrix of ion channels, including one or more acid-sensitive 2-pore domain K channels, could play a role in sour taste transduction. However, our results do not unambiguously identify any one channel as the acid taste transducer.

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37

Mathie, Alistair, Emma L. Veale, Kevin P. Cunningham, Robyn G. Holden, and Paul D. Wright. "Two-Pore Domain Potassium Channels as Drug Targets: Anesthesia and Beyond." Annual Review of Pharmacology and Toxicology 61, no. 1 (January 6, 2021): 401–20. http://dx.doi.org/10.1146/annurev-pharmtox-030920-111536.

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Two-pore domain potassium (K2P) channels stabilize the resting membrane potential of both excitable and nonexcitable cells and, as such, are important regulators of cell activity. There are many conditions where pharmacological regulation of K2P channel activity would be of therapeutic benefit, including, but not limited to, atrial fibrillation, respiratory depression, pulmonary hypertension, neuropathic pain, migraine, depression, and some forms of cancer. Up until now, few if any selective pharmacological regulators of K2P channels have been available. However, recent publications of solved structures with small-molecule activators and inhibitors bound to TREK-1, TREK-2, and TASK-1 K2P channels have given insight into the pharmacophore requirements for compound binding to these sites. Together with the increasing availability of a number of novel, active, small-molecule compounds from K2P channel screening programs, these advances have opened up the possibility of rational activator and inhibitor design to selectively target K2P channels.

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38

Enyedi, Péter, and Gábor Czirják. "Molecular Background of Leak K+ Currents: Two-Pore Domain Potassium Channels." Physiological Reviews 90, no. 2 (April 2010): 559–605. http://dx.doi.org/10.1152/physrev.00029.2009.

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Two-pore domain K+ (K2P) channels give rise to leak (also called background) K+ currents. The well-known role of background K+ currents is to stabilize the negative resting membrane potential and counterbalance depolarization. However, it has become apparent in the past decade (during the detailed examination of the cloned and corresponding native K2P channel types) that this primary hyperpolarizing action is not performed passively. The K2P channels are regulated by a wide variety of voltage-independent factors. Basic physicochemical parameters (e.g., pH, temperature, membrane stretch) and also several intracellular signaling pathways substantially and specifically modulate the different members of the six K2P channel subfamilies (TWIK, TREK, TASK, TALK, THIK, and TRESK). The deep implication in diverse physiological processes, the circumscribed expression pattern of the different channels, and the interesting pharmacological profile brought the K2P channel family into the spotlight. In this review, we focus on the physiological roles of K2P channels in the most extensively investigated cell types, with special emphasis on the molecular mechanisms of channel regulation.

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39

MacKenzie, Georgina, Nicholas P. Franks, and Stephen G. Brickley. "Two-pore domain potassium channels enable action potential generation in the absence of voltage-gated potassium channels." Pflügers Archiv - European Journal of Physiology 467, no. 5 (December 9, 2014): 989–99. http://dx.doi.org/10.1007/s00424-014-1660-6.

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40

Es-Salah-Lamoureux, Zeineb, David F. Steele, and David Fedida. "Research into the therapeutic roles of two-pore-domain potassium channels." Trends in Pharmacological Sciences 31, no. 12 (December 2010): 587–95. http://dx.doi.org/10.1016/j.tips.2010.09.001.

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41

Williams, Sarah, Andrew Bateman, and Ita O'Kelly. "Altered Expression of Two-Pore Domain Potassium (K2P) Channels in Cancer." PLoS ONE 8, no. 10 (October 7, 2013): e74589. http://dx.doi.org/10.1371/journal.pone.0074589.

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42

Şterbuleac, Daniel. "Molecular determinants of chemical modulation of two‐pore domain potassium channels." Chemical Biology & Drug Design 94, no. 3 (June 19, 2019): 1596–614. http://dx.doi.org/10.1111/cbdd.13571.

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43

Talley, Edmund M., Jay E. Sirois, Qiubo Lei, and Douglas A. Bayliss. "Two-Pore-Domain (Kcnk) Potassium Channels: Dynamic Roles in Neuronal Function." Neuroscientist 9, no. 1 (February 2003): 46–56. http://dx.doi.org/10.1177/1073858402239590.

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44

Chow, Gregory E., Charles H. Muller, Eliza C. Curnow, and Eric S. Hayes. "Expression of two-pore domain potassium channels in nonhuman primate sperm." Fertility and Sterility 87, no. 2 (February 2007): 397–404. http://dx.doi.org/10.1016/j.fertnstert.2006.06.051.

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45

Milac, Adina L., Andriy Anishkin, Sarosh N. Fatakia, Carson C. Chow, Sergei Sukharev, and Robert H. Guy. "Structural Models of Two-Pore-Domain Potassium Channels Focus on TREK." Biophysical Journal 98, no. 3 (January 2010): 228a. http://dx.doi.org/10.1016/j.bpj.2009.12.1233.

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46

Trimarchi, James R., Lin Liu, Peter J. S. Smith, and David L. Keefe. "Apoptosis recruits two-pore domain potassium channels used for homeostatic volume regulation." American Journal of Physiology-Cell Physiology 282, no. 3 (March 1, 2002): C588—C594. http://dx.doi.org/10.1152/ajpcell.00365.2001.

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Cell shrinkage is an incipient hallmark of apoptosis and is accompanied by potassium release that decreases the concentration of intracellular potassium and regulates apoptotic progression. The plasma membrane K+channel recruited during apoptosis has not been characterized despite its importance as a potential therapeutic target. Here we provide evidence that two-pore domain K+ (K2P) channels underlie K+ efflux during apoptotic volume decreases (AVD) in mouse embryos. These K2P channels are inhibited by quinine but are not blocked by an array of pharmacological agents that antagonize other K+ channels. The K2P channels are uniquely suited to participate in the early phases of apoptosis because they are not modulated by common intracellular messengers such as calcium, ATP, and arachidonic acid, transmembrane voltage, or the cytoskeleton. A K+channel with similar biophysical properties coordinates regulatory volume decreases (RVD) triggered by changing osmotic conditions. We propose that K2P channels are the pathway by which K+ effluxes during AVD and RVD and that apoptosis co-opts mechanisms more routinely employed for homeostatic cell volume regulation.

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47

Niemeyer, M. I., F. D. González-Nilo, L. Zúñiga, W. González, L. P. Cid, and F. V. Sepúlveda. "Gating of two-pore domain K+ channels by extracellular pH." Biochemical Society Transactions 34, no. 5 (October 1, 2006): 899–902. http://dx.doi.org/10.1042/bst0340899.

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Potassium channels have a conserved selectivity filter that is important in determining which ions are conducted and at what rate. Although K+ channels of different conductance characteristics are known, they differ more widely in the way their opening and closing, the gating, is governed. TASK and TALK subfamily proteins are two-pore region KCNK K+ channels gated open by extracellular pH. We discuss the mechanism for this gating in terms of electrostatic effects on the pore changing the occupancy and open probability of the channels in a way reminiscent of C-type inactivation gating at the selectivity filter. Essential to this proposed mechanism is the replacement of two highly conserved aspartate residues at the pore mouth by asparagine or histidine residues in the TALK and TASK channels.

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Yuill, K. H., P. J. Stansfeld, I. Ashmole, M. J. Sutcliffe, and P. R. Stanfield. "The selectivity, voltage-dependence and acid sensitivity of the tandem pore potassium channel TASK-1: contributions of the pore domains." Pflügers Archiv - European Journal of Physiology 455, no. 2 (June 1, 2007): 333–48. http://dx.doi.org/10.1007/s00424-007-0282-7.

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49

Yost, C. "Tandem Pore Domain K Channels An Important Site of Volatile Anesthetic Action." Current Drug Targets 1, no. 2 (September 1, 2000): 207–17. http://dx.doi.org/10.2174/1389450003349335.

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50

Bina, Robert Wagner, and Steven C. Hempleman. "Evidence for TREK-like tandem-pore domain channels in intrapulmonary chemoreceptor chemotransduction." Respiratory Physiology & Neurobiology 156, no. 2 (May 2007): 120–31. http://dx.doi.org/10.1016/j.resp.2006.09.005.

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