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1
Pondugula, Satyanarayana R., Nithya N. Raveendran, Zuhal Ergonul, et al. "Glucocorticoid regulation of genes in the amiloride-sensitive sodium transport pathway by semicircular canal duct epithelium of neonatal rat." Physiological Genomics 24, no. 2 (2006): 114–23. http://dx.doi.org/10.1152/physiolgenomics.00006.2005.
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The lumen of the inner ear has an unusually low concentration of endolymphatic Na+, which is important for transduction processes. We have recently shown that glucocorticoid receptors (GR) stimulate absorption of Na+ by semicircular canal duct (SCCD) epithelia. In the present study, we sought to determine the presence of genes involved in the control of the amiloride-sensitive Na+ transport pathway in rat SCCD epithelia and whether their level of expression was regulated by glucocorticoids using quantitative real-time RT-PCR. Transcripts were present for α-, β-, and γ-subunits of the epithelial sodium channel (ENaC); the α1-, α3-, β1-, and β3-isoforms of Na+-K+-ATPase; inwardly rectifying potassium channels [IC50 of short circuit current ( Isc) for Ba2+: 210 μM] Kir2.1, Kir2.2, Kir2.3, Kir2.4, Kir3.1, Kir3.3, Kir4.1, Kir4.2, Kir5.1, and Kir7.1; sulfonyl urea receptor 1 (SUR1); GR; mineralocorticoid receptor (MR); 11β-hydroxysteroid dehydrogenase (11β-HSD) types 1 and 2; serum- and glucocorticoid-regulated kinase 1 (Sgk1); and neural precursor cell-expressed developmentally downregulated 4-2 (Nedd4-2). On the other hand, transcripts for the α4-subunit of Na+-K+-ATPase, Kir1.1, Kir3.2, Kir3.4, Kir6.1, Kir6.2, and SUR2 were found to be absent, and Isc was not inhibited by glibenclamide. Dexamethasone (100 nM for 24 h) not only upregulated the transcript expression of α-ENaC (∼4-fold), β2-subunit (∼2-fold) and β3-subunit (∼8-fold) of Na+-K+-ATPase, Kir2.1 (∼5-fold), Kir2.2 (∼9-fold), Kir2.4 (∼3-fold), Kir3.1 (∼ 3- fold), Kir3.3 (∼2-fold), Kir4.2 (∼3-fold ), Kir7.1 (∼2-fold), Sgk1 (∼4-fold), and Nedd4-2 (∼2-fold) but also downregulated GR (∼3-fold) and 11β-HSD1 (∼2-fold). Expression of GR and 11β-HSD1 was higher than MR and 11β-HSD2 in the absence of dexamethasone. Dexamethasone altered transcript expression levels (α-ENaC and Sgk1) by activation of GR but not MR. Proteins were present for the α-, β-, and γ-subunits of ENaC and Sgk1, and expression of α- and γ-ENaC was upregulated by dexamethasone. These findings are consistent with the genomic stimulation by glucocorticoids of Na+ absorption by SCCD and provide an understanding of the therapeutic action of glucocorticoids in the treatment of Meniere's disease.
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Bradley, Karri K., William J. Hatton, Helen S. Mason, et al. "Kir3.1/3.2 encodes an I KACh-like current in gastrointestinal myocytes." American Journal of Physiology-Gastrointestinal and Liver Physiology 278, no. 2 (2000): G289—G296. http://dx.doi.org/10.1152/ajpgi.2000.278.2.g289.
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Expression of the Kir3 channel subfamily in gastrointestinal (GI) myocytes was investigated. Members of this K+ channel subfamily encode G protein-gated inwardly rectifying K+ channels ( I KACh) in other tissues, including the heart and brain. In the GI tract, I KACh could act as a negative feedback mechanism to temper the muscarinic response mediated primarily through activation of nonselective cation currents and inhibition of delayed-rectifier conductance. Kir3 channel subfamily isoforms expressed in GI myocytes were determined by performing RT-PCR on RNA isolated from canine colon, ileum, duodenum, and jejunum circular myocytes. Qualitative PCR demonstrated the presence of Kir3.1 and Kir3.2 transcripts in all smooth muscle cell preparations examined. Transcripts for Kir3.3 and Kir3.4 were not detected in the same preparations. Semiquantitative PCR showed similar transcriptional levels of Kir3.1 and Kir3.2 relative to β-actin expression in the various GI preparations. Full-length cDNAs for Kir3.1 and Kir3.2 were cloned from murine colonic smooth muscle RNA and coexpressed in Xenopus oocytes with human muscarinic type 2 receptor. Superfusion of oocytes with ACh (10 μM) reversibly activated a Ba2+-sensitive and inwardly rectifying K+current. Immunohistochemistry using Kir3.1- and Kir3.2-specific antibodies demonstrated channel expression in circular and longitudinal smooth muscle cells. We conclude that an I KAChcurrent is expressed in GI myocytes encoded by Kir3.1/3.2 heterotetramers.
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Brochiero, Emmanuelle, Bernadette Wallendorf, Dominique Gagnon, Raynald Laprade, and Jean-Yves Lapointe. "Cloning of rabbit Kir6.1, SUR2A, and SUR2B: possible candidates for a renal KATP channel." American Journal of Physiology-Renal Physiology 282, no. 2 (2002): F289—F300. http://dx.doi.org/10.1152/ajprenal.00063.2001.
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In rabbit proximal tubules, a basolateral ATP- and taurine-sensitive K+ channel (KATP) was shown to be involved in the regulation of the basolateral K+ conductance as a function of the rate of apical Na+ entry. To establish the molecular identity of this channel, we used degenerated primers to look for cDNA transcripts for an inwardly rectifying K+ channel (Kir6.1 and Kir6.2) and sulfonylurea receptors (SUR1, SUR2A, and SUR2B) in a cDNA library obtained from rabbit proximal tubules. PCR products were found only for Kir6.1, SUR2A, and SUR2B. Expression of Kir6.1 in Xenopusoocytes generated an additional K+ current that was found to be sensitive to external barium and intracellular taurine and to changes in intracellular ATP concentrations. To study the specificity of the taurine sensitivity, intracellular taurine was tested on several members of the Kir family expressed in Xenopus oocytes. K+ currents induced by Kir1.1A, Kir2.1, Kir3.2, Kir4.1, or Kir5.1 were insensitive to taurine, but all tested combinations of Kir6.x with or without the SUR subunit were significantly inhibited by taurine. This study suggests that the taurine-sensitive KATP channel of rabbit proximal tubules is formed by a combination of Kir6.1 plus SUR2A and/or SUR2B.
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Fang, Yun, Gernot Schram, Victor G. Romanenko, et al. "Functional expression of Kir2.x in human aortic endothelial cells: the dominant role of Kir2.2." American Journal of Physiology-Cell Physiology 289, no. 5 (2005): C1134—C1144. http://dx.doi.org/10.1152/ajpcell.00077.2005.
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Inward rectifier K+ channels (Kir) are a significant determinant of endothelial cell (EC) membrane potential, which plays an important role in endothelium-dependent vasodilatation. In the present study, several complementary strategies were applied to determine the Kir2 subunit composition of human aortic endothelial cells (HAECs). Expression levels of Kir2.1, Kir2.2, and Kir2.4 mRNA were similar, whereas Kir2.3 mRNA expression was significantly weaker. Western blot analysis showed clear Kir2.1 and Kir2.2 protein expression, but Kir2.3 protein was undetectable. Functional analysis of endothelial inward rectifier K+ current ( IK) demonstrated that 1) IK current sensitivity to Ba2+ and pH were consistent with currents determined using Kir2.1 and Kir2.2 but not Kir2.3 and Kir2.4, and 2) unitary conductance distributions showed two prominent peaks corresponding to known unitary conductances of Kir2.1 and Kir2.2 channels with a ratio of ∼4:6. When HAECs were transfected with dominant-negative (dn)Kir2.x mutants, endogenous current was reduced ∼50% by dnKir2.1 and ∼85% by dnKir2.2, whereas no significant effect was observed with dnKir2.3 or dnKir2.4. These studies suggest that Kir2.2 and Kir2.1 are primary determinants of endogenous K+ conductance in HAECs under resting conditions and that Kir2.2 provides the dominant conductance in these cells.
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Konstas, Angelos-Aristeidis, Christoph Korbmacher, and Stephen J. Tucker. "Identification of domains that control the heteromeric assembly of Kir5.1/Kir4.0 potassium channels." American Journal of Physiology-Cell Physiology 284, no. 4 (2003): C910—C917. http://dx.doi.org/10.1152/ajpcell.00479.2002.
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Heteromultimerization between different inwardly rectifying (Kir) potassium channel subunits is an important mechanism for the generation of functional diversity. However, little is known about the mechanisms that control this process and that prevent promiscuous interactions in cells that express many different Kir subunits. In this study, we have examined the heteromeric assembly of Kir5.1 with other Kir subunits and have shown that this subunit exhibits a highly selective interaction with members of the Kir4.0 subfamily and does not physically associate with other Kir subunits such as Kir1.1, Kir2.1, and Kir6.2. Furthermore, we have identified regions within the Kir4.1 subunit that appear to govern the specificity of this interaction. These results help us to understand the mechanisms that control Kir subunit recognition and assembly and how cells can express many different Kir channels while maintaining distinct subpopulations of homo- and heteromeric channels within the cell.
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Yuan, Dou, Ping Zheng, Chen Tan, Si Hui Huang, Dan Li, and Jian Huang. "Influence of Continuous Training on Atrial Myocytes IK1 and IKAch and on Induction of Atrial Fibrillation in a Rabbit Model." Cardiology Research and Practice 2018 (December 19, 2018): 1–10. http://dx.doi.org/10.1155/2018/3795608.
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Background. Elucidation of mechanisms underlying continuous training-related atrial fibrillation (AF) may inform formulation of novel therapeutic approaches and training method selection. This study was aimed at assessing mechanisms underlying continuous training-induced AF in an animal model. Methods. Healthy New Zealand rabbits were divided into three groups (n=8 each), namely, control (C), and moderate intensity (M), and high intensity (H) continuous training according to treadmill speed. Atrial size andintrinsic and resting heart rates were measured by transthoracic echocardiography before, and 8 and 12 weeks after training. Using a Langendorff perfusion system, AF was induced by S1S2 stimulation and the induction rate was recorded. Atrial IK1 and IKAch ion current densities were recorded using whole-cell patch-clamp technique in isolated atrial myocytes. Changes in atrial Kir2.1, Kir2.2, Kir3.1, and Kir3.4 mRNA expression were assessed by reverse transcriptase-coupled polymerase chain reaction. Results. After 8 and 12 weeks, Groups M and H vs. Group C had greater (all P<0.05) atrial anteroposterior diameter; greater incidence of AF (60% and 90% vs. 45%, respectively; P<0.05, also between Groups H and M); and greater atrial IKAch current density. In Group H, Kir2.1 and Kir2.2 mRNA expression in the left and right atria was increased (P<0.05, vs. Groups C and M) as was left atrial Kir3.1 and Kir3.4 mRNA expression (P<0.05, vs. Group C). Conclusion. In a rabbit model, continuous training enlarges atrial diameter leading to atrial structural and electrical remodeling and increased AF incidence.
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Richard-Lalonde, Melissa, Karim Nagi, Nicolas Audet та ін. "Conformational Dynamics of Kir3.1/Kir3.2 Channel Activation Via δ-Opioid Receptors". Molecular Pharmacology 83, № 2 (2012): 416–28. http://dx.doi.org/10.1124/mol.112.081950.
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Leonoudakis, D., W. Mailliard, K. Wingerd, D. Clegg, and C. Vandenberg. "Inward rectifier potassium channel Kir2.2 is associated with synapse-associated protein SAP97." Journal of Cell Science 114, no. 5 (2001): 987–98. http://dx.doi.org/10.1242/jcs.114.5.987.
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The strong inwardly rectifying potassium channels Kir2.x are involved in maintenance and control of cell excitability. Recent studies reveal that the function and localization of ion channels are regulated by interactions with members of the membrane-associated guanylate kinase (MAGUK) protein family. To identify novel interacting MAGUK family members, we constructed GST-fusion proteins with the C termini of Kir2.1, Kir2.2 and Kir2.3. GST affinity-pulldown assays from solubilized rat cerebellum and heart membrane proteins revealed an interaction between all three Kir2.x C-terminal fusion proteins and the MAGUK protein synapse-associated protein 97 (SAP97). A truncated form of the C-terminal GST-Kir2.2 fusion protein indicated that the last three amino acids (S-E-I) are essential for association with SAP97. Affinity interactions using GST-fusion proteins containing the modular domains of SAP97 demonstrate that the second PSD-95/Dlg/ZO-1 (PDZ) domain is sufficient for interaction with Kir2.2. Coimmunoprecipitations demonstrated that endogenous Kir2.2 associates with SAP97 in rat cerebellum and heart. Additionally, phosphorylation of the Kir2.2 C terminus by protein kinase A inhibited the association with SAP97. In rat cardiac ventricular myocytes, Kir2.2 and SAP97 colocalized in striated bands corresponding to T-tubules. In rat cerebellum, Kir2.2 was present in a punctate pattern along SAP97-positive processes of Bergmann glia in the molecular layer, and colocalized with astrocytes and granule cells in the granule cell layer. These results identify a direct association of Kir2.1, Kir2.2 and Kir2.3 with the MAGUK family member SAP97 that may form part of a macromolecular signaling complex in many different tissues.
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Szuts, Viktoria, Dalma Ménesi, Zoltán Varga-Orvos, et al. "Altered expression of genes for Kir ion channels in dilated cardiomyopathy." Canadian Journal of Physiology and Pharmacology 91, no. 8 (2013): 648–56. http://dx.doi.org/10.1139/cjpp-2012-0413.
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Dilated cardiomyopathy (DCM) is a multifactorial disease characterized by left ventricular dilation that is associated with systolic dysfunction and increased action potential duration. The Kir2.x K+ channels (encoded by KCNJ genes) regulate the inward rectifier current (IK1) contributing to the final repolarization in cardiac muscle. Here, we describe the transitions in the gene expression profiles of 4 KCNJ genes from healthy or dilated cardiomyopathic human hearts. In the healthy adult ventricles, KCNJ2, KCNJ12, and KCNJ4 (Kir2.1–2.3, respectively) genes were expressed at high levels, while expression of the KCNJ14 (Kir2.4) gene was low. In DCM ventricles, the levels of Kir2.1 and Kir2.3 were upregulated, but those of Kir2.2 channels were downregulated. Additionally, the expression of the DLG1 gene coding for the synapse-associated protein 97 (SAP97) anchoring molecule exhibited a 2-fold decline with increasing age in normal hearts, and it was robustly downregulated in young DCM patients. These adaptations could offer a new aspect for the explanation of the generally observed physiological and molecular alterations found in DCM.
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Masia, Ricard, Daniela S. Krause, and Gary Yellen. "The inward rectifier potassium channel Kir2.1 is expressed in mouse neutrophils from bone marrow and liver." American Journal of Physiology-Cell Physiology 308, no. 3 (2015): C264—C276. http://dx.doi.org/10.1152/ajpcell.00176.2014.
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Neutrophils are phagocytic cells that play a critical role in innate immunity by destroying bacterial pathogens. Channels belonging to the inward rectifier potassium channel subfamily 2 (Kir2 channels) have been described in other phagocytes (monocytes/macrophages and eosinophils) and in hematopoietic precursors of phagocytes. Their physiological function in these cells remains unclear, but some evidence suggests a role in growth factor-dependent proliferation and development. Expression of functional Kir2 channels has not been definitively demonstrated in mammalian neutrophils. Here, we show by RT-PCR that neutrophils from mouse bone marrow and liver express mRNA for the Kir2 subunit Kir2.1 but not for other subunits (Kir2.2, Kir2.3, and Kir2.4). In electrophysiological experiments, resting (unstimulated) neutrophils from mouse bone marrow and liver exhibit a constitutively active, external K+-dependent, strong inwardly rectifying current that constitutes the dominant current. The reversal potential is dependent on the external K+ concentration in a Nernstian fashion, as expected for a K+-selective current. The current is not altered by changes in external or internal pH, and it is blocked by Ba2+, Cs+, and the Kir2-selective inhibitor ML133. The single-channel conductance is in agreement with previously reported values for Kir2.1 channels. These properties are characteristic of homomeric Kir2.1 channels. Current density in short-term cultures of bone marrow neutrophils is decreased in the absence of growth factors that are important for neutrophil proliferation [granulocyte colony-stimulating factor (G-CSF) and stem cell factor (SCF)]. These results demonstrate that mouse neutrophils express functional Kir2.1 channels and suggest that these channels may be important for neutrophil function, possibly in a growth factor-dependent manner.
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Huang, Chunfa, Aleksandra Sindic, Ceredwyn E. Hill, et al. "Interaction of the Ca2+-sensing receptor with the inwardly rectifying potassium channels Kir4.1 and Kir4.2 results in inhibition of channel function." American Journal of Physiology-Renal Physiology 292, no. 3 (2007): F1073—F1081. http://dx.doi.org/10.1152/ajprenal.00269.2006.
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The Ca2+-sensing receptor (CaR), a G protein-coupled receptor, is expressed in many epithelial tissues including the parathyroid glands, kidney, and GI tract. Although its role in regulating PTH levels and Ca2+ metabolism are best characterized, it may also regulate salt and water transport in the kidney as demonstrated by recent reports showing association of potent gain-of-function mutations in the CaR with a Bartter-like, salt-wasting phenotype. To determine whether this receptor interacts with novel proteins that control ion transport, we screened a human adult kidney cDNA library with the COOH-terminal 219 amino acid cytoplasmic tail of the CaR as bait using the yeast two-hybrid system. We identified two independent clones coding for ∼125 aa from the COOH terminus of the inwardly rectifying K+ channel, Kir4.2. The CaR and Kir4.2 as well as Kir4.1 (another member of Kir4 subfamily) were reciprocally coimmunoprecipitated from HEK-293 cells in which they were expressed, but the receptor did not coimmunoprecipitate with Kir5.1 or Kir1.1. Both Kir4.1 and Kir4.2 were immunoprecipitated from rat kidney extracts with the CaR. In Xenopus laevis oocytes, expression of the CaR with either Kir4.1 or Kir4.2 channels resulted in inactivation of whole cell current as measured by two-electrode voltage clamp, but the nonfunctional CaR mutant CaRR796W, and that does not coimmunoprecipitate with the channels, had no effect. Kir4.1 and the CaR were colocalized in the basolateral membrane of the distal nephron. The CaR interacts directly with Kir4.1 and Kir4.2 and can decrease their currents, which in turn could reduce recycling of K+ for the basolateral Na+-K+-ATPase and thereby contribute to inhibition of Na+ reabsorption.
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Panama, Brian K., Meredith McLerie, and Anatoli N. Lopatin. "Heterogeneity of IK1 in the mouse heart." American Journal of Physiology-Heart and Circulatory Physiology 293, no. 6 (2007): H3558—H3567. http://dx.doi.org/10.1152/ajpheart.00419.2007.
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Previous studies have shown that cardiac inward rectifier potassium current ( IK1) channels are heteromers of distinct Kir2 subunits and suggested that species- and tissue-dependent expression of these subunits may underlie variability of IK1. In this study, we investigated the contribution of the slowly activating Kir2.3 subunit and free intracellular polyamines (PAs) to variability of IK1 in the mouse heart. The kinetics of activation was measured in Kir2 concatemeric tetramers with known subunit stoichiometry. Inclusion of only one Kir2.3 subunit to a Kir2.1 channel led to an approximate threefold slowing of activation kinetics, with greater slowing on subsequent additions of Kir2.3 subunits. Activation kinetics of IK1 in both ventricles and both atria was found to correspond to fast-activating Kir2.1/Kir2.2 channels, suggesting no major contribution of Kir2.3 subunits. In contrast, IK1 displayed significant variation in both the current density and inward rectification, suggesting involvement of intracellular PAs. The total levels of PAs were similar across the mouse heart. Measurements of the free intracellular PAs in isolated myocytes, using transgenically expressed Kir2.1 channels as PA sensors, revealed “microheterogeneity” of IK1 rectification as well as lower levels of free PAs in atrial myocytes compared with ventricular cells. These findings provide a quantitative explanation for the regional heterogeneity of IK1.
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Brasko, Csilla, and Arthur Butt. "Expression of Kir2.1 Inward Rectifying Potassium Channels in Optic Nerve Glia: Evidence for Heteromeric Association with Kir4.1 and Kir5.1." Neuroglia 1, no. 1 (2018): 176–87. http://dx.doi.org/10.3390/neuroglia1010012.
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Inward rectifying potassium (Kir) channels comprise a large family with diverse biophysical properties. A predominant feature of central nervous system (CNS) glia is their expression of Kir4.1, which as homomers are weakly rectifying channels, but form strongly rectifying channels as heteromers with Kir2.1. However, the extent of Kir2.1 expression and their association with Kir4.1 in glia throughout the CNS is unclear. We have examined this in astrocytes and oligodendrocytes of the mouse optic nerve, a typical CNS white matter tract. Western blot and immunocytochemistry demonstrates that optic nerve astrocytes and oligodendrocytes express Kir2.1 and that it co-localises with Kir4.1. Co-immunoprecipitation analysis provided further evidence that Kir2.1 associate with Kir4.1 and, moreover, Kir2.1 expression was significantly reduced in optic nerves and brains from Kir4.1 knock-out mice. In addition, optic nerve glia express Kir5.1, which may associate with Kir2.1 to form silent channels. Immunocytochemical and co-immunoprecipitation analyses indicate that Kir2.1 associate with Kir5.1 in optic nerve glia, but not in the brain. The results provide evidence that astrocytes and oligodendrocytes may express heteromeric Kir2.1/Kir4.1 and Kir2.1/Kir5.1 channels, together with homomeric Kir2.1 and Kir4.1 channels. In astrocytes, expression of multiple Kir channels is the biophysical substrate for the uptake and redistribution of K+ released during neuronal electrical activity known as ‘potassium spatial buffering’. Our findings suggest a similar potential role for the diverse Kir channels expressed by oligodendrocytes, which by way of their myelin sheaths are intimately associated with the sites of action potential propagation and axonal K+ release.
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Kamikawa, Akihiro, and Toru Ishikawa. "Functional expression of a Kir2.1-like inwardly rectifying potassium channel in mouse mammary secretory cells." American Journal of Physiology-Cell Physiology 306, no. 3 (2014): C230—C240. http://dx.doi.org/10.1152/ajpcell.00219.2013.
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K+ channels in mammary secretory (MS) cells are believed to play a role in transcellular electrolyte transport and thus determining ionic composition of the aqueous phase of milk. However, direct evidence for specific K+ channel activity in native MS cells is lacking at the single-cell level. Here, we show for the first time that an inwardly rectifying K+ (Kir) channel is functionally expressed in fully differentiated MS cells that were freshly isolated from the mammary gland of lactating mice. Using the standard whole cell patch-clamp technique, we found that mouse MS cells consistently displayed a K+ current, whose electrophysiological properties are similar to those previously reported for Kir2.x channels, particularly Kir2.1: 1) current-voltage relationship with strong inward rectification, 2) slope conductance approximately proportional to the square root of external K+ concentration, 3) voltage- and time-dependent and high-affinity block by external Ba2+, and 4) voltage-dependent inhibition by external Cs+. Accordingly, RT-PCR analysis revealed the gene expression of Kir2.1, but not Kir2.2, Kir2.3, and Kir2.4, in lactating mouse mammary gland, and immunohistochemical staining showed Kir2.1 protein expression in the secretory cells. Cell-attached patch recordings from MS cells revealed that a 31-pS K+ channel with strong inward rectification was likely active at the resting membrane potential. Collectively, the present work demonstrates that a functional Kir2.1-like channel is expressed in lactating mouse MS cells. We propose that the channel might be involved, at least in part, in secretion and/or preservation of ionic components of milk stored into the lumen of these cells.
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Weaver, C. David, and Jerod S. Denton. "Next-generation inward rectifier potassium channel modulators: discovery and molecular pharmacology." American Journal of Physiology-Cell Physiology 320, no. 6 (2021): C1125—C1140. http://dx.doi.org/10.1152/ajpcell.00548.2020.
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Inward rectifying potassium (Kir) channels play important roles in both excitable and nonexcitable cells of various organ systems and could represent valuable new drug targets for cardiovascular, metabolic, immune, and neurological diseases. In nonexcitable epithelial cells of the kidney tubule, for example, Kir1.1 ( KCNJ1) and Kir4.1 ( KCNJ10) are linked to sodium reabsorption in the thick ascending limb of Henle’s loop and distal convoluted tubule, respectively, and have been explored as novel-mechanism diuretic targets for managing hypertension and edema. G protein-coupled Kir channels (Kir3) channels expressed in the central nervous system are critical effectors of numerous signal transduction pathways underlying analgesia, addiction, and respiratory-depressive effects of opioids. The historical dearth of pharmacological tool compounds for exploring the therapeutic potential of Kir channels has led to a molecular target-based approach using high-throughput screen (HTS) of small-molecule libraries and medicinal chemistry to develop “next-generation” Kir channel modulators that are both potent and specific for their targets. In this article, we review recent efforts focused specifically on discovery and improvement of target-selective molecular probes. The reader is introduced to fluorescence-based thallium flux assays that have enabled much of this work and then provided with an overview of progress made toward developing modulators of Kir1.1 (VU590, VU591), Kir2.x (ML133), Kir3.X (ML297, GAT1508, GiGA1, VU059331), Kir4.1 (VU0134992), and Kir7.1 (ML418). We discuss what is known about the small molecules’ molecular mechanisms of action, in vitro and in vivo pharmacology, and then close with our view of what critical work remains to be done.
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Zhang, Changliang, Takashi Miki, Tadao Shibasaki, Masaaki Yokokura, Atsunori Saraya, and Susumu Seino. "Identification and characterization of a novel member of the ATP-sensitive K+ channel subunit family, Kir6.3, in zebrafish." Physiological Genomics 24, no. 3 (2006): 290–97. http://dx.doi.org/10.1152/physiolgenomics.00228.2005.
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ATP-sensitive K+ (KATP) channels play a crucial role in coupling cellular metabolism to membrane potential. In addition to the orthologs corresponding to Kir6.1 and Kir6.2 of mammals, we have identified a novel member, designated Kir6.3 (zKir6.3), of the inward rectifier K+ channel subfamily Kir6.x in zebrafish. zKir6.3 is a protein of 432 amino acids that shares 66% identity with mammalian Kir6.2 but differs considerably from mammalian Kir6.1 and Kir6.2 in the COOH terminus, which contain an Arg-Lys-Arg (RKR) motif, an endoplasmic reticulum (ER) retention signal. Single-channel recordings of reconstituted channels show that zKir6.3 requires the sulfonylurea receptor 1 (SUR1) subunit to produce KATP channel currents with single-channel conductance of 57.5 pS. Confocal microscopic analysis shows that zebrafish Kir6.3 requires the SUR1 subunit for its trafficking to the plasma membrane. Analyses of chimeric protein between human Kir6.2 and zKir6.3 and a COOH-terminal deletion of zKir6.3 indicate that interaction between the COOH terminus of zKir6.3 and SUR1 is critical for both channel activity and trafficking to the plasma membrane. We also identified zebrafish orthologs corresponding to mammalian SUR1 (zSUR1) and SUR2 (zSUR2) by the genomic database. Both Kir6.3 and SUR1 are expressed in embryonic brain of zebrafish, as assessed by whole mount in situ hybridization. These data indicate that Kir6.3 and SUR1 form functional KATP channels at the plasma membrane in zebrafish through a mechanism independent from ER retention by the RKR motif.
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Lignon, Jacques M., Zoë Bichler, Bruno Hivert, et al. "Altered heart rate control in transgenic mice carrying the KCNJ6 gene of the human chromosome 21." Physiological Genomics 33, no. 2 (2008): 230–39. http://dx.doi.org/10.1152/physiolgenomics.00143.2007.
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Congenital heart defects (CHD) are common in Down syndrome (DS, trisomy 21). Recently, cardiac sympathetic-parasympathetic imbalance has also been documented in DS adults free of any CHD. The KCNJ6 gene located on human chromosome 21 encodes for the Kir3.2/GIRK2 protein subunits of G protein-regulated K+ (KG) channels and could contribute to this altered cardiac regulation. To elucidate the role of its overexpression, we used homozygous transgenic (Tg+/+) mice carrying copies of human KCNJ6. These mice showed human Kir3.2 mRNA expression in the heart and a 2.5-fold increased translation in the atria. Phenotypic alterations were assessed by recording electrocardiogram of urethane anesthetized mice. Chronotropic responses to direct (carbachol) and indirect (methoxamine) muscarinic stimulation were enhanced in Tg+/+ mice with respect to wild-type (WT) mice. Alternating periods of slow and fast rhythm induced by CCPA (2-chloro- N-cyclopentyl-adenosine) were amplified in Tg+/+ mice, resulting in a reduced negative chronotropic effect. These drugs reduced the atrial P wave amplitude and area. P wave variations induced by methoxamine and CCPA were respectively increased and reduced in the Tg+/+ mice, while PR interval and ventricular wave showed no difference between Tg+/+ and WT. These results indicate that Tg+/+ mice incorporating the human KCNJ6 exhibit altered Kir3.2 expression and responses to drugs that would activate KG channels. Moreover, these altered expression and responses are limited to sino-atrial node and atria that normally express large amounts of KG channels. These data suggest that KCNJ6 could play an important role in altered cardiac regulation in DS patients.
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Tang, Chengchun, Dong Wang, Erfei Luo, et al. "Activation of Inward Rectifier K+ Channel 2.1 by PDGF-BB in Rat Vascular Smooth Muscle Cells through Protein Kinase A." BioMed Research International 2020 (May 2, 2020): 1–9. http://dx.doi.org/10.1155/2020/4370832.
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Platelet-derived growth factor-BB (PDGF-BB) can induce the proliferation, migration, and phenotypic modulation of vascular smooth muscle cells (VSMCs). We used patch clamp methods to study the effects of PDGF-BB on inward rectifier K+ channel 2.1 (Kir2.1) channels in rat thoracic aorta VSMCs (RASMCs). PDGF-BB (25 ng/mL) increased Kir2.x currents (−11.81±2.47 pA/pF, P<0.05 vs. CON, n=10). Ba2+(50 μM) decreased Kir2.x currents (−2.13±0.23 pA/pF, P<0.05 vs. CON, n=10), which were promoted by PDGF-BB (−6.98±1.03 pA/pF). PDGF-BB specifically activates Kir2.1 but not Kir2.2 and Kir2.3 channels in HEK-293 cells. The PDGF-BB-induced stimulation of Kir2.1 currents was blocked by the PDGF-BB receptor β (PDGF-BBRβ) inhibitor AG1295 and was not affected by the PDGF-BBRα inhibitor AG1296. The PDGF-BB-induced stimulation of Kir2.1 currents was blocked by the protein kinase A inhibitor Rp-8-CPT-cAMPs; however, the antagonist of protein kinase B (GSK690693) had marginal effects on current activity. The PDGF-BB-induced stimulation of Kir2.1 currents was enhanced by forskolin, an adenylyl cyclase (AC) activator, and was blocked by the AC inhibitor SQ22536. We conclude that PDGF-BB increases Kir2.1 currents via PDGF-BBRβ through activation of cAMP-PKA signaling in RASMCs.
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Akyuz, Enes, Chiara Villa, Merve Beker та Birsen Elibol. "Unraveling the Role of Inwardly Rectifying Potassium Channels in the Hippocampus of an Aβ(1–42)-Infused Rat Model of Alzheimer’s Disease". Biomedicines 8, № 3 (2020): 58. http://dx.doi.org/10.3390/biomedicines8030058.
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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with a complex etiology and characterized by cognitive deficits and memory loss. The pathogenesis of AD is not yet completely elucidated, and no curative treatment is currently available. Inwardly rectifying potassium (Kir) channels are important for playing a key role in maintaining the resting membrane potential and controlling cell excitability, being largely expressed in both excitable and non-excitable tissues, including neurons. Accordingly, the aim of the study is to investigate the role of neuronal Kir channels in AD pathophysiology. The mRNA and protein levels of neuronal Kir2.1, Kir3.1, and Kir6.2 were evaluated by real-time PCR and Western blot analysis from the hippocampus of an amyloid-β(Aβ)(1-42)-infused rat model of AD. Extracellular deposition of Aβ was confirmed by both histological Congo red staining and immunofluorescence analysis. Significant decreased mRNA and protein levels of Kir2.1 and Kir6.2 channels were observed in the rat model of AD, whereas no differences were found in Kir3.1 channel levels as compared with controls. Our results provide in vivo evidence that Aβ can modulate the expression of these channels, which may represent novel potential therapeutic targets in the treatment of AD.
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Qiao, Pei, Yang Liu, Tianqi Zhang, Amanda Benavides, and Arthur Laganowsky. "Insight into the Selectivity of Kir3.2 toward Phosphatidylinositides." Biochemistry 59, no. 22 (2020): 2089–99. http://dx.doi.org/10.1021/acs.biochem.0c00163.
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Dobrzynski, Halina, David D. R. Marples, Hanny Musa, et al. "Distribution of the Muscarinic K+ Channel Proteins Kir3.1 and Kir3.4 in the Ventricle, Atrium, and Sinoatrial Node of Heart." Journal of Histochemistry & Cytochemistry 49, no. 10 (2001): 1221–34. http://dx.doi.org/10.1177/002215540104901004.
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The functionally important effects on the heart of ACh released from vagal nerves are principally mediated by the muscarinic K+ channel. The aim of this study was to determine the abundance and cellular location of the muscarinic K+ channel subunits Kir3.1 and Kir3.4 in different regions of heart. Western blotting showed a very low abundance of Kir3.1 in rat ventricle, although Kir3.1 was undetectable in guinea pig and ferret ventricle. Although immunofluorescence on tissue sections showed no labeling of Kir3.1 in rat, guinea pig, and ferret ventricle and Kir3.4 in rat ventricle, immunofluorescence on single ventricular cells from rat showed labeling in t-tubules of both Kir3.1 and Kir3.4. Kir3.1 was abundant in the atrium of the three species, as shown by Western blotting and immunofluorescence, and Kir3.4 was abundant in the atrium of rat, as shown by immunofluorescence. Immunofluorescence showed Kir3.1 expression in SA node from the three species and Kir3.4 expression in the SA node from rat. The muscarinic K+ channel is activated by ACh via the m2 muscarinic receptor and, in atrium and SA node from ferret, Kir3.1 labeling was co-localized with m2 muscarinic receptor labeling throughout the outer cell membrane.
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Patel, Dharmeshkumar, Serdar Kuyucak, and Craig A. Doupnik. "Structural Determinants Mediating Tertiapin Block of Neuronal Kir3.2 Channels." Biochemistry 59, no. 7 (2020): 836–50. http://dx.doi.org/10.1021/acs.biochem.9b01098.
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Doupnik, Craig A., Dharmeshkumar Patel, and Serdar Kuyucak. "Validation of computational models for tertiapin-blocked neuronal Kir3.2 channels." Toxicon 159 (March 2019): S7. http://dx.doi.org/10.1016/j.toxicon.2018.11.336.
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Stary-Weinzinger, Anna, and Harald Bernsteiner. "Conduction and Selectivity in Kir3.2 Channels - A Molecular Dynamics Study." Biophysical Journal 118, no. 3 (2020): 108a. http://dx.doi.org/10.1016/j.bpj.2019.11.741.
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Torrecilla, Maria, Cheryl L. Marker, Stephanie C. Cintora, Markus Stoffel, John T. Williams, and Kevin Wickman. "G-Protein-Gated Potassium Channels Containing Kir3.2 and Kir3.3 Subunits Mediate the Acute Inhibitory Effects of Opioids on Locus Ceruleus Neurons." Journal of Neuroscience 22, no. 11 (2002): 4328–34. http://dx.doi.org/10.1523/jneurosci.22-11-04328.2002.
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Delgado-Ramírez, Mayra, Fanny Junue Rodriguez-Leal, Aldo Azmar Rodríguez-Menchaca, Eloy Gerardo Moreno-Galindo, José Antonio Sanchez-Chapula, and Tania Ferrer. "Inhibitory effect of terfenadine on Kir2.1 and Kir2.3 channels." Acta Pharmaceutica 71, no. 2 (2020): 317–24. http://dx.doi.org/10.2478/acph-2021-0017.
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Abstract Terfenadine is a second-generation H1-antihistamine that despite potentially can produce severe side effects it has recently gained attention due to its anticancer properties. Lately, the subfamily 2 of inward rectifier potassium channels (Kir2) has been implicated in the progression of some tumoral processes. Hence, we characterized the effects of terfenadine on Kir2.x channels expressed in HEK-293 cells. Terfenadine inhibited Kir2.3 channels with a strikingly greater potency (IC 50 = 1.06 ± 0.11 μmol L−1) compared to Kir2.1 channels (IC 50 = 27.8 ± 4.8 μmol L−1). The Kir2.3(I213L) mutant, possessing a larger affinity for phosphatidylinositol 4,5-bisphosphate (PIP2) than the wild-type Kir2.3, was less sensitive to terfenadine inhibition (IC 50 = 13.0 ± 2.9 μmol L−1). Additionally, the PIP2 intracellular application had largely reduced the inhibition of Kir2.1 channels by terfenadine. Our data support that Kir2.x channels are targets of terfena-dine by affecting their interaction with PIP2, which could be regarded as a mechanism of the antitumor properties of terfenadine.
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Friesacher, Theres, Harald Bernsteiner, and Anna Stary-Weinzinger. "Structural Changes in Kir3.2 Channels Leading to Loss of K+ Selectivity." Biophysical Journal 120, no. 3 (2021): 244a. http://dx.doi.org/10.1016/j.bpj.2020.11.1596.
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Adney, Scott K., Xuan-Yu Meng, and Diomedes E. Logothetis. "Unique PIP2 Sensitivity at a Putative PKC Site in GIRK2 (Kir3.2)." Biophysical Journal 104, no. 2 (2013): 130a. http://dx.doi.org/10.1016/j.bpj.2012.11.745.
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Li, Daxu, Rong Chen, and Shin-Ho Chung. "Molecular dynamics of the honey bee toxin tertiapin binding to Kir3.2." Biophysical Chemistry 219 (December 2016): 43–48. http://dx.doi.org/10.1016/j.bpc.2016.09.010.
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Kawano, Takashi, Shuzo Oshita, Akira Takahashi, et al. "Molecular Mechanisms Underlying Ketamine-mediated Inhibition of Sarcolemmal Adenosine Triphosphate-sensitive Potassium Channels." Anesthesiology 102, no. 1 (2005): 93–101. http://dx.doi.org/10.1097/00000542-200501000-00017.
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Background Ketamine inhibits adenosine triphosphate-sensitive potassium (KATP) channels, which results in the blocking of ischemic preconditioning in the heart and inhibition of vasorelaxation induced by KATP channel openers. In the current study, the authors investigated the molecular mechanisms of ketamine's actions on sarcolemmal KATP channels that are reassociated by expressed subunits, inwardly rectifying potassium channels (Kir6.1 or Kir6.2) and sulfonylurea receptors (SUR1, SUR2A, or SUR2B). Methods The authors used inside-out patch clamp configurations to investigate the effects of ketamine on the activities of reassociated Kir6.0/SUR channels containing wild-type, mutant, or chimeric SURs expressed in COS-7 cells. Results Ketamine racemate inhibited the activities of the reassociated KATP channels in a SUR subtype-dependent manner: SUR2A/Kir6.2 (IC50 = 83 microM), SUR2B/Kir6.1 (IC50 = 77 microM), SUR2B/Kir6.2 (IC50 = 89 microM), and SUR1/Kir6.2 (IC50 = 1487 microM). S-(+)-ketamine was significantly less potent than ketamine racemate in blocking all types of reassociated KATP channels. The ketamine racemate and S-(+)-ketamine both inhibited channel currents of the truncated isoform of Kir6.2 (Kir6.2DeltaC36) with very low affinity. Application of 100 mum magnesium adenosine diphosphate significantly enhanced the inhibitory potency of ketamine racemate. The last transmembrane domain of SUR2 was essential for the full inhibitory effect of ketamine racemate. Conclusions These results suggest that ketamine-induced inhibition of sarcolemmal KATP channels is mediated by the SUR subunit. These inhibitory effects of ketamine exhibit specificity for cardiovascular KATP channels, at least some degree of stereoselectivity, and interaction with intracellular magnesium adenosine diphosphate.
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Miki, T., K. Nagashima, and S. Seino. "The structure and function of the ATP-sensitive K+ channel in insulin-secreting pancreatic beta-cells." Journal of Molecular Endocrinology 22, no. 2 (1999): 113–23. http://dx.doi.org/10.1677/jme.0.0220113.
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ATP-sensitive K+ channels (KATP channels) play important roles in many cellular functions by coupling cell metabolism to electrical activity. The KATP channels in pancreatic beta-cells are thought to be critical in the regulation of glucose-induced and sulfonylurea-induced insulin secretion. Until recently, however, the molecular structure of the KATP channel was not known. Cloning members of the novel inwardly rectifying K+ channel subfamily Kir6.0 (Kir6.1 and Kir6.2) and the sulfonylurea receptors (SUR1 and SUR2) has clarified the molecular structure of KATP channels. The pancreatic beta-cell KATP channel comprises two subunits: a Kir6.2 subunit and an SUR1 subunit. Molecular biological and molecular genetic studies have provided insights into the physiological and pathophysiological roles of the pancreatic beta-cell KATP channel in insulin secretion.
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Hassinen, Minna, Vesa Paajanen, Jaakko Haverinen, Heli Eronen, and Matti Vornanen. "Cloning and expression of cardiac Kir2.1 and Kir2.2 channels in thermally acclimated rainbow trout." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 292, no. 6 (2007): R2328—R2339. http://dx.doi.org/10.1152/ajpregu.00354.2006.
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Potassium currents are plastic entities that modify electrical activity of the heart in various physiological conditions including chronic thermal stress. We examined the molecular basis of the inward rectifier K+ current ( IK1) in rainbow trout acclimated to cold (4°C, CA) and warm (18°C, WA) temperature. Inward rectifier K+ channel (Kir)2.1 and Kir2.2 transcripts were expressed in atrium and ventricle of the trout heart, Kir2.1 being the major component in both cardiac chambers. The relative expression of Kir2.2 was, however, higher ( P < 0.05) in atrium than ventricle. The density of ventricular IK1 was ∼25% larger ( P < 0.05) in WA than CA trout. Furthermore, the IK1 of the WA trout was 10 times more sensitive to Ba2+ (IC50 0.18 ± 0.42 μM) than the IK1 of the CA trout (1.17 ± 0.44 μM) ( P < 0.05), and opening kinetics of single Kir2 channels was slower in WA than CA trout ( P < 0.05). When expressed in COS-1 cells, the homomeric Kir2.2 channels demonstrated higher Ba2+ sensitivity (2.88 ± 0.42 μM) than Kir2.1 channels (24.99 ± 7.40 μM) ( P < 0.05). In light of the different Ba2+ sensitivities of rainbow trout (om)Kir2.1 and omKir2.2 channels, it is concluded that warm acclimation increases either number or activity of the omKir2.2 channels in trout ventricular myocytes. The functional changes in IK1 are independent of omKir2 transcript levels, which remained unaltered by thermal acclimation. Collectively, these findings suggest that thermal acclimation modifies functional properties and subunit composition of the trout Kir2 channels, which may be needed for regulation of cardiac excitability at variable temperatures.
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Yang, Hua-Qian, Wilnelly Martinez-Ortiz, JongIn Hwang, Xuexin Fan, Timothy J. Cardozo, and William A. Coetzee. "Palmitoylation of the KATP channel Kir6.2 subunit promotes channel opening by regulating PIP2 sensitivity." Proceedings of the National Academy of Sciences 117, no. 19 (2020): 10593–602. http://dx.doi.org/10.1073/pnas.1918088117.
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A physiological role for long-chain acyl-CoA esters to activate ATP-sensitive K+ (KATP) channels is well established. Circulating palmitate is transported into cells and converted to palmitoyl-CoA, which is a substrate for palmitoylation. We found that palmitoyl-CoA, but not palmitic acid, activated the channel when applied acutely. We have altered the palmitoylation state by preincubating cells with micromolar concentrations of palmitic acid or by inhibiting protein thioesterases. With acyl-biotin exchange assays we found that Kir6.2, but not sulfonylurea receptor (SUR)1 or SUR2, was palmitoylated. These interventions increased the KATP channel mean patch current, increased the open time, and decreased the apparent sensitivity to ATP without affecting surface expression. Similar data were obtained in transfected cells, rat insulin-secreting INS-1 cells, and isolated cardiac myocytes. Kir6.2ΔC36, expressed without SUR, was also positively regulated by palmitoylation. Mutagenesis of Kir6.2 Cys166 prevented these effects. Clinical variants in KCNJ11 that affect Cys166 had a similar gain-of-function phenotype, but was more pronounced. Molecular modeling studies suggested that palmitoyl-C166 and selected large hydrophobic mutations make direct hydrophobic contact with Kir6.2-bound PIP2. Patch-clamp studies confirmed that palmitoylation of Kir6.2 at Cys166 enhanced the PIP2 sensitivity of the channel. Physiological relevance is suggested since palmitoylation blunted the regulation of KATP channels by α1-adrenoreceptor stimulation. The Cys166 residue is conserved in some other Kir family members (Kir6.1 and Kir3, but not Kir2), which are also subject to regulated palmitoylation, suggesting a general mechanism to control the open state of certain Kir channels.
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Кожевникова, Л. М., and И. Ф. Суханова. "Aging has different effects on the functional activity and gene expression of classical inward-rectifying potassium channels Kir2.1 and Kir2.4 and ATP-sensitive KATP channels in blood vessels and heart of male rats." Zhurnal «Patologicheskaia fiziologiia i eksperimental`naia terapiia» 67, no. 2 (2023): 5–16. http://dx.doi.org/10.25557/0031-2991.2023.02.5-16.
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Старение и связанные с ним дисрегуляционные процессы в артериях и сердце являются ведущими предикторами развития сердечно-сосудистых заболеваний. Важную роль в регуляции сократимости сосудов и миокарда играют ионные каналы. Цель исследования – изучение влияния возраста на функциональную активность и экспрессию генов классических калиевых каналов внутреннего выпрямления Kir2.1 и Kir2.4, а также КATP каналов в аорте и сердце крыс. Методика. Эксперименты проводили на крысах самцах Wistar в возрасте 3 и 18 мес. Силу сокращения грудного отдела аорты измеряли в изометрическом режиме, экспрессию генов оценивали при помощи ПЦР анализа. Результаты. Установлено, что у крыс в возрасте 18 мес в аорте снижается функциональная активность Kir2.1 и Kir2.4 каналов, в то время как уровень экспрессии этих каналов остается неизменным. В стареющих сердцах, напротив, выявлен высокий уровень экспрессии генов Kir2.1 и Kir2.4 каналов. Показано, что KATP каналы не влияют на серотонин-индуцированное сокращение аорты молодых крыс (3 мес), но вносят существенный вклад в развитие гиперчувствительности старых сосудов к вазоконстрикторному действию серотонина. Так, блокада KATP каналов глибенкламидом приводила к статистически значимому смещению зависимости «концентрация-эффект» на серотонин вправо только в аорте возрастных крыс. Выявлено возрастное снижение экспрессии генов порообразующей Kir6.2 и регуляторной Sur2 субъединиц KATP канала в аорте и, напротив, значительное повышение в сердце крыс. Заключение. Полученные результаты свидетельствуют о ранних возрастных изменениях функциональной активности калиевых каналов внутреннего выпрямления Kir 2.1 и Kir 2.4, а также KATP каналов в аорте крыс самцов, которые в процессе дальнейшего старения сосудов могут способствовать развитию гипертензии. Предположено, что гиперэкспрессия Kir2.4 и Kir2.1 каналов в стареющем сердце может инициировать нарушения сократительной функции миокарда и возникновение аритмий в старости, в то время как высокий уровень экспрессии субъединиц KATP является показателем компенсаторно-адаптивных процессов, направленных на повышение устойчивости миокарда к гипоксии и стрессу. Aging and related dysregulatory processes in the arteries and heart are the sleading predictors of cardiovascular diseases. Ion channels play an important role in the regulation of vascular and myocardial contractility. The aim of the study was to investigate the effect of age on the functional activity and gene expression of classical inward-rectifying potassium channels Kir2.1 and Kir2.4, as well as KATP channels in the aorta and heart of rats. Methods. Experiments were performed on Wistar male rats at 3 and 18 months of age. The force of thoracic aorta contractions was measured isometrically, and the gene expression was assessed by PCR analysis. Results. In the aorta of 18-month-old rats, the functional activity of Kir2.1 and Kir2.4 channels was reduced while the expression of these channels remained unchanged. In the aging hearts, on the contrary, the expression level of Kir2.1 and Kir2.4 channel genes was high. The KATP channels had no effect on serotonin-induced aortic contractions in young, 3-month-old rats, but contributed significantly to the development of hypersensitivity of aging blood vessels to serotonin-induced vasoconstriction. Thus, blockade of KATP channels with glibenclamide led to a significant shift of the concentration-effect curve of serotonin to the right only for the aorta from old rats. Age-related decreases in the gene expression of pore-forming Kir6.2 and regulatory Sur2 subunits of the KATP channel were observed in the aorta, and, vice versa, significant increases in their expression were observed in the rat heart. Conclusion. The study results indicated early age-related changes in the functional activity of Kir 2.1 and Kir 2.4 inward-rectifying potassium channels, as well as of KATP channels in the aorta of male rat. During further vascular aging, these changes may contribute to the development of hypertension. It was suggested that Kir2.4 and Kir2.1 channel overexpression in the aging heart may initiate disorders of myocardial contractility and arrhythmias in older age. At the same time, a high level of KATP subunit expression indicates compensatory-adaptive processes aimed at increasing myocardial resistance to hypoxia and stress.
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Ishihara, Keiko, Tomomi Yamamoto, and Yoshihiro Kubo. "Heteromeric assembly of inward rectifier channel subunit Kir2.1 with Kir3.1 and with Kir3.4." Biochemical and Biophysical Research Communications 380, no. 4 (2009): 832–37. http://dx.doi.org/10.1016/j.bbrc.2009.01.179.
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Zhou, Ming, Osamu Tanaka, Masaki Sekiguchi, et al. "ATP-sensitive K+ -channel Subunits on the Mitochondria and Endoplasmic Reticulum of Rat Cardiomyocytes." Journal of Histochemistry & Cytochemistry 53, no. 12 (2005): 1491–500. http://dx.doi.org/10.1369/jhc.5a6736.2005.
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ATP-sensitive K+ (KATP) channel subunits on the subcellular structures of rat cardiomyocytes were studied with antibodies against Kir6.1 and Kir6.2. According to the results of Western blot analysis, Kir6.1 was strongly expressed in mitochondrial and microsome fractions, and faintly expressed in cell membrane fraction, whereas Kir6.2 was mainly expressed in the microsome fraction and weakly in cell membrane and mitochondrial fractions. Immunohistochemistry showed that Kir6.1 and Kir6.2 were expressed in the endocardium, atrial and ventricular myocardium, and in vascular smooth muscles. Immunoelectron microscopy revealed that Kir6.1 immunoreactivity was mainly localized in the mitochondria, whereas Kir6.2 immunoreactivity was mainly localized in the endoplasmic reticulum and a few in the mitochondria. Both Kir6.1 and Kir6.2 are candidates of mitochondrial KATP channel subunits. The data obtained in this study will be useful for analyzing the composition of KATP channels of cardiomyocytes and help to understanding the cardioprotective role of KATP channels during heart ischemia.
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Owen, J. M., C. C. Quinn, R. Leach, J. B. C. Findlay, and M. R. Boyett. "Effect of Extracellular Cations on the Inward Rectifying K+ Channels Kir2.1 and Kir3.1/Kir3.4." Experimental Physiology 84, no. 3 (1999): 471–88. http://dx.doi.org/10.1111/j.1469-445x.1999.01806.x.
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Bagriantsev, Sviatoslav N., Franck C. Chatelain, Kimberly A. Clark, Noga Alagem, Eitan Reuveny, and Daniel L. Minor. "Tethered Protein Display Identifies a Novel Kir3.2 (GIRK2) Regulator from Protein Scaffold Libraries." ACS Chemical Neuroscience 5, no. 9 (2014): 812–22. http://dx.doi.org/10.1021/cn5000698.
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Hilder, Tamsyn A., and Shin-Ho Chung. "Conductance properties of the inwardly rectifying channel, Kir3.2: Molecular and Brownian dynamics study." Biochimica et Biophysica Acta (BBA) - Biomembranes 1828, no. 2 (2013): 471–78. http://dx.doi.org/10.1016/j.bbamem.2012.09.022.
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Taylor, Clinton A., Sung-Wan An, Sachith Gallolu Kankanamalage, et al. "OSR1 regulates a subset of inward rectifier potassium channels via a binding motif variant." Proceedings of the National Academy of Sciences 115, no. 15 (2018): 3840–45. http://dx.doi.org/10.1073/pnas.1802339115.
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The with-no-lysine (K) (WNK) signaling pathway to STE20/SPS1-related proline- and alanine-rich kinase (SPAK) and oxidative stress-responsive 1 (OSR1) kinase is an important mediator of cell volume and ion transport. SPAK and OSR1 associate with upstream kinases WNK 1–4, substrates, and other proteins through their C-terminal domains which interact with linear R-F-x-V/I sequence motifs. In this study we find that SPAK and OSR1 also interact with similar affinity with a motif variant, R-x-F-x-V/I. Eight of 16 human inward rectifier K+ channels have an R-x-F-x-V motif. We demonstrate that two of these channels, Kir2.1 and Kir2.3, are activated by OSR1, while Kir4.1, which does not contain the motif, is not sensitive to changes in OSR1 or WNK activity. Mutation of the motif prevents activation of Kir2.3 by OSR1. Both siRNA knockdown of OSR1 and chemical inhibition of WNK activity disrupt NaCl-induced plasma membrane localization of Kir2.3. Our results suggest a mechanism by which WNK-OSR1 enhance Kir2.1 and Kir2.3 channel activity by increasing their plasma membrane localization. Regulation of members of the inward rectifier K+ channel family adds functional and mechanistic insight into the physiological impact of the WNK pathway.
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Nakamura, Tomoe Y., Michael Artman, Bernardo Rudy, and William A. Coetzee. "Inhibition of rat ventricularI K1 with antisense oligonucleotides targeted to Kir2.1 mRNA." American Journal of Physiology-Heart and Circulatory Physiology 274, no. 3 (1998): H892—H900. http://dx.doi.org/10.1152/ajpheart.1998.274.3.h892.
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The cardiac inward rectifying K+ current ( I K1) is important in maintaining the maximum diastolic potential. We used antisense oligonucleotides to determine the role of Kir2.1 channel proteins in the genesis of native rat ventricular I K1. A combination of two antisense phosphorothioate oligonucleotides inhibited heterologously expressed Kir2.1 currents in Xenopus oocytes, either when coinjected with Kir2.1 cRNA or when applied in the incubation medium. Specificity was demonstrated by the lack of inhibition of Kir2.2 and Kir2.3 currents in oocytes. In rat ventricular myocytes (4–5 days culture), these oligonucleotides caused a significant reduction of whole cell I K1(without reducing the transient outward K+ current or the L-type Ca2+ current). Cell-attached patches demonstrated the occurrence of multiple channel events in control myocytes (8, 14, 21, 35, 43, and 80 pS). The 21-pS channel was specifically knocked down in antisense-treated myocytes (fewer patches contained this channel, and its open frequency was reduced). These results demonstrate that the Kir2.1 gene encodes a specific native 21-pS K+-channel protein and that this channel has an essential role in the genesis of cardiac I K1.
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Wang, Ming-Xiao, Xiao-Tong Su, Peng Wu, et al. "Kir5.1 regulates Nedd4-2-mediated ubiquitination of Kir4.1 in distal nephron." American Journal of Physiology-Renal Physiology 315, no. 4 (2018): F986—F996. http://dx.doi.org/10.1152/ajprenal.00059.2018.
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Kir4.1/5.1 heterotetramer participates in generating the negative cell membrane potential in distal convoluted tubule (DCT) and plays a critical role in determining the activity of Na-Cl cotransporter (NCC). Kir5.1 contains a phosphothreonine motif at its COOH terminus (AA249–252). Coimmunoprecipitation showed that Nedd4-2 was associated with Kir5.1 in HEK293 cells cotransfected with Kir5.1 or Kir4.1/Kir5.1. GST pull-down further confirmed the association between Nedd4-2 and Kir5.1. Ubiquitination assay showed that Nedd4-2 increased the ubiquitination of Kir4.1/Kir5.1 heterotetramer in the cells cotransfected with Kir4.1/Kir5.1, but it has no effect on Kir4.1 or Kir5.1 alone. Patch-clamp and Western blot also demonstrated that coexpression of Nedd4-2 but not Nedd4-1 decreased K currents and Kir4.1 expression in the cells cotransfected with Kir4.1 and Kir5.1. In contrast, Nedd4-2 fails to inhibit Kir4.1 in the absence of Kir5.1 or in the cells transfected with the inactivated form of Nedd4-2 (Nedd4-2C821A). Moreover, the mutation of TPVT motif in the COOH terminus of Kir5.1 largely abolished the association of Nedd4-2 with Kir5.1 and abolished the inhibitory effect of Nedd4-2 on K currents in HEK293 cells transfected with Kir4.1 and Kir5.1 mutant (Kir5.1T249A). Finally, the basolateral K conductance in the DCT and Kir4.1 expression is significantly increased in the kidney-specific Nedd4-2 knockout or in Kir5.1 knockout mice in comparison to their corresponding wild-type littermates. We conclude that Nedd4-2 binds to Kir5.1 at the phosphothreonine motif of the COOH terminus, and the association of Nedd4-2 with Kir5.1 facilitates the ubiquitination of Kir4.1, thereby regulating its plasma expression in the DCT.
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Ishii, Masaru, Akikazu Fujita, Kaori Iwai, et al. "Differential expression and distribution of Kir5.1 and Kir4.1 inwardly rectifying K+ channels in retina." American Journal of Physiology-Cell Physiology 285, no. 2 (2003): C260—C267. http://dx.doi.org/10.1152/ajpcell.00560.2002.
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Kir5.1 is an inwardly rectifying K+ channel subunit whose functional role has not been fully elucidated. Expression and distribution of Kir5.1 in retina were examined with a specific polyclonal antibody. Kir5.1 immunoreactivity was detected in glial Müller cells and in some retinal neurons. In the Kir5.1-positive neurons the expression of glutamic acid decarboxylase (GAD65) was detected, suggesting that they may be GABAergic-amacrine cells. In Müller cells, spots of Kir5.1 immunoreactivity distributed diffusely at the cell body and in the distal portions, where Kir4.1 immunoreactivity largely overlapped. In addition, Kir4.1 immunoreactivity without Kir5.1 was strongly concentrated at the endfoot of Müller cells facing the vitreous surface or in the processes surrounding vessels. The immunoprecipitant obtained from retina with anti-Kir4.1 antibody contained Kir5.1. These results suggest that heterotetrameric Kir4.1/Kir5.1 channels may exist in the cell body and distal portion of Müller cells, whereas homomeric Kir4.1 channels are clustered in the endfeet and surrounding vessels. It is possible that homomeric Kir4.1 and heteromeric Kir4.1/Kir5.1 channels play different functional roles in the K+-buffering action of Müller cells.
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Tanemoto, Masayuki, Takaaki Abe, Tohru Onogawa, and Sadayoshi Ito. "PDZ binding motif-dependent localization of K+ channel on the basolateral side in distal tubules." American Journal of Physiology-Renal Physiology 287, no. 6 (2004): F1148—F1153. http://dx.doi.org/10.1152/ajprenal.00203.2004.
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Kir5.1, a nonfunctional inwardly rectifying K+ channel by itself, can form functional channels by assembling with other proteins. We previously showed that Kir5.1 assembled with Kir4.1 and functioned as an acid-base regulator in the kidney. In this study, we examined the intrarenal distribution of Kir5.1 by RT-PCR analysis on dissected nephron segments and immunohistochemical analysis with the specific anti-Kir5.1 antibody. Strong expression of Kir5.1 was detected in distal convoluted tubules, and weak expression was also detected in thick ascending limb of Henle's loop. Colocalization of Kir5.1 with Kir4.1 indicated expression of Kir5.1/Kir4.1 heteromer in these nephron segments. In a renal epithelial cell line, Madin-Darby canine kidney cells, heteromer formation with Kir4.1 changed the localization of Kir5.1 from intracellular components to the cell surface. The COOH-terminal cytoplasmic portion that includes the PDZ binding motif of Kir4.1 was responsible for this intracellular localization. These data suggest the signals on the COOH terminus of Kir4.1, including PDZ binding motif, determine the intracellular localization of Kir5.1/Kir4.1 heteromer in distal tubules.
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Hassinen, Minna, Hanna Korajoki, Denis Abramochkin, Pavel Krivosheya, and Matti Vornanen. "Transcript expression of inward rectifier potassium channels of Kir2 subfamily in Arctic marine and freshwater fish species." Journal of Comparative Physiology B 189, no. 6 (2019): 735–49. http://dx.doi.org/10.1007/s00360-019-01241-9.
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Abstract Inward rectifier K+ (Kir2) channels are critical for electrical excitability of cardiac myocytes. Here, we examine expression of Kir2 channels in the heart of three Gadiformes species, polar cod (Boreogadus saida) and navaga (Eleginus nawaga) of the Arctic Ocean and burbot (Lota lota) of the temperate lakes to find out the role of Kir2 channels in cardiac adaptation to cold. Five boreal freshwater species: brown trout (Salmo trutta fario), arctic char (Salvelinus alpinus), roach (Rutilus rutilus), perch (Perca fluviatilis) and pike (Esox lucius), and zebrafish (Danio rerio), were included for comparison. Transcript expression of genes encoding Kir2.1a, − 2.1b, − 2.2a, − 2.2b and − 2.4 was studied from atrium and ventricle of thermally acclimated or acclimatized fish by quantitative PCR. Kir2 composition in the polar cod was more diverse than in other species in that all Kir2 isoforms were relatively highly expressed. Kir2 composition of navaga and burbot differed from that of the polar cod as well as from those of other species. The relative expression of Kir2.2 transcripts, especially Kir2.2b, was higher in both atrium and ventricle of navaga and burbot (56–89% from the total Kir2 pool) than in other species (0.1–11%). Thermal acclimation induced only small changes in cardiac Kir2 transcript expression in Gadiformes species. However, Kir2.2b transcripts were upregulated in cold-acclimated navaga and burbot hearts. All in all, the cardiac Kir2 composition seems to be dependent on both phylogenetic position and thermal preference of the fish.
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Walsh, Kenneth B. "Screening Technologies for Inward Rectifier Potassium Channels: Discovery of New Blockers and Activators." SLAS DISCOVERY: Advancing the Science of Drug Discovery 25, no. 5 (2020): 420–33. http://dx.doi.org/10.1177/2472555220905558.
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K+ channels play a critical role in maintaining the normal electrical activity of excitable cells by setting the cell resting membrane potential and by determining the shape and duration of the action potential. In nonexcitable cells, K+ channels establish electrochemical gradients necessary for maintaining salt and volume homeostasis of body fluids. Inward rectifier K+ (Kir) channels typically conduct larger inward currents than outward currents, resulting in an inwardly rectifying current versus voltage relationship. This property of inward rectification results from the voltage-dependent block of the channels by intracellular polyvalent cations and makes these channels uniquely designed for maintaining the resting potential near the K+ equilibrium potential (EK). The Kir family of channels consist of seven subfamilies of channels (Kir1.x through Kir7.x) that include the classic inward rectifier (Kir2.x) channel, the G-protein-gated inward rectifier K+ (GIRK) (Kir3.x), and the adenosine triphosphate (ATP)-sensitive (KATP) (Kir 6.x) channels as well as the renal Kir1.1 (ROMK), Kir4.1, and Kir7.1 channels. These channels not only function to regulate electrical/electrolyte transport activity, but also serve as effector molecules for G-protein-coupled receptors (GPCRs) and as molecular sensors for cell metabolism. Of significance, Kir channels represent promising pharmacological targets for treating a number of clinical conditions, including cardiac arrhythmias, anxiety, chronic pain, and hypertension. This review provides a brief background on the structure, function, and pharmacology of Kir channels and then focuses on describing and evaluating current high-throughput screening (HTS) technologies, such as membrane potential-sensitive fluorescent dye assays, ion flux measurements, and automated patch clamp systems used for Kir channel drug discovery.
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Kawano, Takashi, Shuzo Oshita, Akira Takahashi, et al. "Molecular Mechanisms of the Inhibitory Effects of Propofol and Thiamylal on Sarcolemmal Adenosine Triphosphate–sensitive Potassium Channels." Anesthesiology 100, no. 2 (2004): 338–46. http://dx.doi.org/10.1097/00000542-200402000-00024.
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Background Both propofol and thiamylal inhibit adenosine triphosphate-sensitive potassium (KATP) channels. In the current study, the authors investigated the effects of these anesthetics on the activity of recombinant sarcolemmal KATP channels encoded by inwardly rectifying potassium channel (Kir6.1 or Kir6.2) genes and sulfonylurea receptor (SUR1, SUR2A, or SUR2B) genes. Methods The authors used inside-out patch clamp configurations to investigate the effects of propofol and thiamylal on the activity of recombinant KATP channels using COS-7 cells transfected with various types of KATP channel subunits. Results Propofol inhibited the activities of the SUR1/Kir6.2 (EC50 = 77 microm), SUR2A/Kir6.2 (EC50 = 72 microm), and SUR2B/Kir6.2 (EC50 = 71 microm) channels but had no significant effects on the SUR2B/Kir6.1 channels. Propofol inhibited the truncated isoform of Kir6.2 (Kir6.2DeltaC36) channels (EC50 = 78 microm) that can form functional KATP channels in the absence of SUR molecules. Furthermore, the authors identified two distinct mutations R31E (arginine residue at position 31 to glutamic acid) and K185Q (lysine residue at position 185 to glutamine) of the Kir6.2DeltaC36 channel that significantly reduce the inhibition of propofol. In contrast, thiamylal inhibited the SUR1/Kir6.2 (EC50 = 541 microm), SUR2A/Kir6.2 (EC50 = 248 microm), SUR2B/Kir6.2 (EC50 = 183 microm), SUR2B/Kir6.1 (EC50 = 170 microm), and Kir6.2DeltaC36 channels (EC50 = 719 microm). None of the mutants significantly affects the sensitivity of thiamylal. Conclusions These results suggest that the major effects of both propofol and thiamylal on KATP channel activity are mediated via the Kir6.2 subunit. Site-directed mutagenesis study suggests that propofol and thiamylal may influence Kir6.2 activity by different molecular mechanisms; in thiamylal, the SUR subunit seems to modulate anesthetic sensitivity.
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Maqoud, Fatima, Rosa Scala, Vincenzo Tragni, et al. "Zoledronic Acid as a Novel Dual Blocker of KIR6.1/2-SUR2 Subunits of ATP-Sensitive K+ Channels: Role in the Adverse Drug Reactions." Pharmaceutics 13, no. 9 (2021): 1350. http://dx.doi.org/10.3390/pharmaceutics13091350.
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Zoledronic acid (ZOL) is used as a bone-specific antiresorptive drug with antimyeloma effects. Adverse drug reactions (A.D.R.) are associated with ZOL-therapy, whose mechanics are unknown. ZOL is a nitrogen-containing molecule whose structure shows similarities with nucleotides, ligands of ATP-sensitive K+ (KATP) channels. We investigated the action of ZOL by performing in vitro patch-clamp experiments on native KATP channels in murine skeletal muscle fibers, bone cells, and recombinant subunits in cell lines, and by in silico docking the nucleotide site on KIR and SUR, as well as the glibenclamide site. ZOL fully inhibited the KATP currents recorded in excised macro-patches from Extensor digitorum longus (EDL) and Soleus (SOL) muscle fibers with an IC50 of 1.2 ± 1.4 × 10−6 and 2.1 ± 3.7 × 10−10 M, respectively, and the KATP currents recorded in cell-attached patches from primary long bone cells with an IC50 of 1.6 ± 2.8 × 10−10 M. ZOL fully inhibited a whole-cell KATP channel current of recombinant KIR6.1-SUR2B and KIR6.2-SUR2A subunits expressed in HEK293 cells with an IC50 of 3.9 ± 2.7 × 10−10 M and 7.1 ± 3.1 × 10−6 M, respectively. The rank order of potency in inhibiting the KATP currents was: KIR6.1-SUR2B/SOL-KATP/osteoblast-KATP > KIR6.2-SUR2A/EDL-KATP >>> KIR6.2-SUR1 and KIR6.1-SUR1. Docking investigation revealed that the drug binds to the ADP/ATP sites on KIR6.1/2 and SUR2A/B and on the sulfonylureas site showing low binding energy <6 Kcal/mol for the KIR6.1/2-SUR2 subunits vs. the <4 Kcal/mol for the KIR6.2-SUR1. The IC50 of ZOL to inhibit the KIR6.1/2-SUR2A/B channels were correlated with its musculoskeletal and cardiovascular risks. We first showed that ZOL blocks at subnanomolar concentration musculoskeletal KATP channels and cardiac and vascular KIR6.2/1-SUR2 channels.
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Seyler, C., P. Xynogalos, D. Scherer, et al. "P639Amiodarone and dronedarone inhibit inwardly rectifying Kir2.1 channels, but not Kir2.2 and Kir2.3 channels." Cardiovascular Research 103, suppl 1 (2014): S116.3—S116. http://dx.doi.org/10.1093/cvr/cvu098.66.
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Wu, Peng, Zhong-Xiuzi Gao, Xiao-Tong Su, Ming-Xiao Wang, Wen-Hui Wang, and Dao-Hong Lin. "Kir4.1/Kir5.1 Activity Is Essential for Dietary Sodium Intake–Induced Modulation of Na-Cl Cotransporter." Journal of the American Society of Nephrology 30, no. 2 (2018): 216–27. http://dx.doi.org/10.1681/asn.2018080799.
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BackgroundDietary sodium intake regulates the thiazide-sensitive Na-Cl cotransporter (NCC) in the distal convoluted tubule (DCT). Whether the basolateral, inwardly rectifying potassium channel Kir4.1/Kir5.1 (a heterotetramer of Kir4.1/Kir5.1) in the DCT is essential for mediating the effect of dietary sodium intake on NCC activity is unknown.MethodsWe used electrophysiology, renal clearance techniques, and immunoblotting to examine effects of Kir4.1/Kir5.1 in the DCT and NCC in wild-type and kidney-specific Kir4.1 knockout mice.ResultsLow sodium intake stimulated basolateral Kir4.1/Kir5.1 activity, increased basolateral K+ conductance, and hyperpolarized the membrane. Conversely, high sodium intake inhibited the potassium channel, decreased basolateral K+ currents, and depolarized the membrane. Low sodium intake increased total and phosphorylated NCC expression and augmented hydrochlorothiazide-induced natriuresis; high sodium intake had opposite effects. Thus, elevated NCC activity induced by low sodium intake was associated with upregulation of Kir4.1/Kir5.1 activity in the DCT, whereas inhibition of NCC activity by high sodium intake was associated with diminished Kir4.1/Kir5.1 activity. In contrast, dietary sodium intake did not affect NCC activity in knockout mice. Further, Kir4.1 deletion not only abolished basolateral K+ conductance and depolarized the DCT membrane, but also abrogated the stimulating effects induced by low sodium intake on basolateral K+ conductance and hyperpolarization. Finally, dietary sodium intake did not alter urinary potassium excretion rate in hypokalemic knockout and wild-type mice.ConclusionsStimulation of Kir4.1/Kir5.1 by low intake of dietary sodium is essential for NCC upregulation, and inhibition of Kir4.1/Kir5.1 induced by high sodium intake is a key step for downregulation of NCC.