Funktionelle Analyse der Kir3.4-Kanalvarianten Kir3.4R332* und Kir3.4V137M - Molekulare Grundlagen KCNJ5-assoziierter Herzrhythmusstörungen
Loading...
Date
Authors
Publisher
Supervisors
Abstract
The gene KCNJ5, which encodes for the inward rectifying potassium channel Kir3.4, carries several already known pathogenic variants. These can lead, among others, to different types of cardiac arrhythmias. The gain of function variant W101C was described as responsible for causing a familial sinus node disease. This study now describes and characterizes a new variant (V137M) that could also be responsible for a familial sinus node disease in an autosomal dominant inheritance. The index patient suffered from a sick sinus syndrome with bradycardias up to a heart rate of 25/min. She was heterozygous for Kir3.4V137M.
Our electrophysiological findings with Kir3.4V137M expressed in oocytes of Xenopus laevis showed a strong gain of function compared to the wild type. Paired with the M2 muscarinic acetylcholine receptor, the activation of Kir3.4V137M with acetylcholine significantly decreased compared to Kir3.4WT. A direct influence on the Kir3.4 binding site of G proteins Gβγ though does not appear to be likely, as amino acid position 137 is located inside the Kir3.4 extracellular pore helix. In previous findings, only variants located in the cytosol were connected to a direct influence on the binding of Gβγ. Furthermore, our findings showed neither an increase in Kir3.4V137M cell surface expression nor a loss of potassium selectivity responsible for the gain of function. Therefore, a modified gating of the mutant channel is most likely causal. This could be, like the pathological mechanism of Kir3.4W101C, caused by a change in the binding site of Mg2+ ions. The latter are essential for the inward rectifying characteristics of the channel. This hypothesis can be further evaluated in future studies.
Additionally, a homozygous variant in Kir3.4 (R332*) was described and characterized for the first time. The associated index patient showed a temporary prolonged QT interval. Both parents carried the heterozygous variant Kir3.4R332*. This nonsense mutation introduces a premature stop codon at position 332 in Kir3.4R332*, so all following amino acids are lost. The current amplitude measurements showed a striking loss-of-function for Kir3.4R332* with almost no measurable current. Surface expression data showed that the mutant channel does not reach the cellular membrane. This could, on the one hand, be caused by a loss of the necessary signal sequence (consisting of the amino acids 350 – 399), which is highly relevant for the transport of the Kir3.1/Kir3.4 heterotetramer to the cell surface. On the other hand, a premature degradation of the protein by the proteasome is also possible. Further studies can differentiate between these two.
Overall, a total loss-of-function of the Kir3.4 subunit was seen. The index patient, however, presented with a just temporarily prolonged QT interval. Afterwards there have been no more cardiac symptoms reported. That leads to the thesis that a total loss of the Kir3.4 protein might be more favourable for the organism than a change in function as it is seen in different pathogen variants (for example in Kir3.4V137M). Previous experiments with knockout mice, which lack the Kir3.4 protein, support this thesis as they did not express a large change in their cardiac phenotype compared to the wild type.
Summarized, this study analysed the functional effects of two new Kir3.4 protein variants and correlated them with the patients’ symptoms, especially well for Kir3.4V137M. The collected data can pave the way for new molecular therapies of cardiac arrhythmias. Just one example are inhibitors of inward rectifying potassium channels that are currently being researched.
Review
Metadata
Contributors
Supervisor:
Dates
Issued: 2026-06-16
Relations
Has part: Ackerman, M.J., Priori, S.G., Willems, S., Berul, C., Brugada, R., Calkins, H., Camm, A.J., Ellinor, P.T., Gollob, M., Hamilton, R., Hershberger, R.E., Judge, D.P., Le Marec, H., McKenna, W.J., Schulze-Bahr, E., Semsarian, C., Towbin, J.A., Watkins, H., Wilde, A., Wolpert, C., and Zipes, D.P. (2011). HRS/EHRA Expert Consensus Statement on the State of Genetic Testing for the Channelopathies and Cardiomyopathies: This document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). EP Eur 13, 1077–1109. DOI: 10.1093/europace/eur245. Adler, A., Novelli, V., Amin, A.S., Abiusi, E., Care, M., Nannenberg, E.A., Feilotter, H., Amenta, S., Mazza, D., Bikker, H., Sturm, A.C., Garcia, J., Ackerman, M.J., Hershberger, R.E., Perez, M.V., Zareba, W., Ware, J.S., Wilde, A.A.M., and Gollob, M.H. (2020). An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome. Circulation 141, 418–428. DOI: 10.1161/CIRCULATIONAHA.119.043132. Adzhubei, I.A., Schmidt, S., Peshkin, L., Ramensky, V.E., Gerasimova, A., Bork, P., Kondrashov, A.S., and Sunyaev, S.R. (2010). A method and server for predicting damaging missense mutations. Nat Methods 7, 248–249. DOI: 10.1038/nmeth0410-248. Åkerström, T., Crona, J., Verdugo, A.D., Starker, L.F., Cupisti, K., Willenberg, H.S., Knoefel, W.T., Saeger, W., Feller, A., Ip, J., Soon, P., Anlauf, M., Alesina, P.F., Schmid, K.W., Decaussin, M., Levillain, P., Wängberg, B., Peix, J.-L., Robinson, B., Zedenius, J., Bäckdahl, M., Caramuta, S., Iwen, K.A., Botling, J., Stålberg, P., et al. (2012). Comprehensive Re-Sequencing of Adrenal Aldosterone Producing Lesions Reveal Three Somatic Mutations near the KCNJ5 Potassium Channel Selectivity Filter. PLOS ONE 7, e41926. DOI: 10.1371/journal.pone.0041926. Anderson, A., Kulkarni, K., Marron Fernandez de Velasco, E., Carlblom, N., Xia, Z., Nakano, A., Martemyanov, K.A., Tolkacheva, E.G., and Wickman, K. (2018). Expression and relevance of the G protein-gated K+ channel in the mouse ventricle. Sci Rep 8, 1192. DOI: 10.1038/s41598-018-19719-x. Anderson, A., Vo, B.N., Velasco, E.M.F. de, Hopkins, C.R., Weaver, C.D., and Wickman, K. (2021). Characterization of VU0468554, a New Selective Inhibitor of Cardiac G Protein–Gated Inwardly Rectifying K+ Channels. Mol Pharmacol 100, 540–547. DOI: 10.1124/molpharm.121.000311. Benson, D.W., Wang, D.W., Dyment, M., Knilans, T.K., Fish, F.A., Strieper, M.J., Rhodes, T.H., and George, A.L. (2003). Congenital sick sinus syndrome caused by recessive mutations in the cardiac sodium channel gene (SCN5A). J Clin Invest 112, 1019–1028. DOI: 10.1172/JCI18062. Brohawn, S.G., del Mármol, J., and MacKinnon, R. (2012). Crystal structure of the human K2P TRAAK, a lipid- and mechano-sensitive K+ ion channel. Science 335, 436–441. DOI: 10.1126/science.1213808. Brown, A.M., Lee, K.S., and Powell, T. (1981). Sodium current in single rat heart muscle cells. J Physiol 318, 479–500. DOI: 10.1113/jphysiol.1981.sp013879. Calloe, K., Ravn, L.S., Schmitt, N., Sui, J.L., Duno, M., Haunso, S., Grunnet, M., Svendsen, J.H., and Olesen, S.-P. (2007). Characterizations of a loss-of-function mutation in the Kir3.4 channel subunit. Biochem Biophys Res Commun 364, 889–895. DOI: 10.1016/j.bbrc.2007.10.106. Charmandari, E., Sertedaki, A., Kino, T., Merakou, C., Hoffman, D.A., Hatch, M.M., Hurt, D.E., Lin, L., Xekouki, P., Stratakis, C.A., and Chrousos, G.P. (2012). A Novel Point Mutation in the KCNJ5 Gene Causing Primary Hyperaldosteronism and Early-Onset Autosomal Dominant Hypertension. J Clin Endocrinol Metab 97, E1532–E1539. DOI: 10.1210/jc.2012-1334. Chen, S., Francioli, L.C., Goodrich, J.K., Collins, R.L., Kanai, M., Wang, Q., Alföldi, J., Watts, N.A., Vittal, C., Gauthier, L.D., Poterba, T., Wilson, M.W., Tarasova, Y., Phu, W., Yohannes, M.T., Koenig, Z., Farjoun, Y., Banks, E., Donnelly, S., Gabriel, S., Gupta, N., Ferriera, S., Tolonen, C., Novod, S., Bergelson, L., et al. (2022). A genome-wide mutational constraint map quantified from variation in 76,156 human genomes. 2022.03.20.485034. Choi, M., Scholl, U.I., Yue, P., Björklund, P., Zhao, B., Nelson-Williams, C., Ji, W., Cho, Y., Patel, A., Men, C.J., Lolis, E., Wisgerhof, M.V., Geller, D.S., Mane, S., Hellman, P., Westin, G., Åkerström, G., Wang, W., Carling, T., and Lifton, R.P. (2011). K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science 331, 768–772. DOI: 10.1126/science.1198785. Chueh, J.S., Peng, K.-Y., Wu, V.-C., Wang, S.-M., Chan, C.-K., Chen, Y.-M., Ke, Y.-Y., Pan, C.-Y., and Liao, H.-W. (2021). Characterization of a mutated KCNJ5 gene, G387R, in unilateral primary aldosteronism. J Mol Endocrinol 67, 203–215. DOI: 10.1530/JME-20-0282. Claydon, T.W., Makary, S.Y., Dibb, K.M., and Boyett, M.R. (2003). The Selectivity Filter May Act as the Agonist-activated Gate in the G Protein-activated Kir3.1/Kir3.4 K+ Channel*. J Biol Chem 278, 50654–50663. DOI: 10.1074/jbc.M308183200. Corey, S., and Clapham, D.E. (1998). Identification of Native Atrial G-protein-regulated Inwardly Rectifying K+ (GIRK4) Channel Homomultimers*. J Biol Chem 273, 27499–27504. DOI: 10.1074/jbc.273.42.27499. Dhamoon, A.S., Pandit, S.V., Sarmast, F., Parisian, K.R., Guha, P., Li, Y., Bagwe, S., Taffet, S.M., and Anumonwo, J.M.B. (2004). Unique Kir2.x properties determine regional and species differences in the cardiac inward rectifier K+ current. Circ Res 94, 1332–1339. DOI: 10.1161/01.RES.0000128408.66946.67. DiFrancesco, D. (1981). A new interpretation of the pace-maker current in calf Purkinje fibres. J Physiol 314, 359–376. DOI: 10.1113/jphysiol.1981.sp013713. DiFrancesco, D., and Mangoni, M. (1994). Modulation of single hyperpolarization-activated channels (i(f)) by cAMP in the rabbit sino-atrial node. J Physiol 474, 473–482. Dobrev, D., Friedrich, A., Voigt, N., Jost, N., Wettwer, E., Christ, T., Knaut, M., and Ravens, U. (2005). The G Protein–Gated Potassium Current IK,ACh Is Constitutively Active in Patients With Chronic Atrial Fibrillation. Circulation 112, 3697–3706. DOI: 10.1161/CIRCULATIONAHA.105.575332. Doupnik, C.A., Davidson, N., Lester, H.A., and Kofuji, P. (1997). RGS proteins reconstitute the rapid gating kinetics of Gβγ-activated inwardly rectifying K+ channels. Proc Natl Acad Sci 94, 10461–10466. DOI: 10.1073/pnas.94.19.10461. Ferrer, M.I. (1968). The Sick Sinus Syndrome in Atrial Disease. JAMA 206, 645–646. DOI: 10.1001/jama.1968.03150030101028. Ferrer, J., Nichols, C.G., Makhina, E.N., Salkoff, L., Bernstein, J., Gerhard, D., Wasson, J., Ramanadham, S., and Permutt, A. (1995). Pancreatic Islet Cells Express a Family of Inwardly Rectifying K+ Channel Subunits Which Interact to Form G-protein-activated Channels (∗). J Biol Chem 270, 26086–26091. DOI: 10.1074/jbc.270.44.26086. Frischmeyer, P.A., and Dietz, H.C. (1999). Nonsense-Mediated mRNA Decay in Health and Disease. Hum Mol Genet 8, 1893–1900. DOI: 10.1093/hmg/8.10.1893. Gaborit, S, L.B., V, S., A, V., D, E., S, N., and S, D. (2007). Regional and tissue specific transcript signatures of ion channel genes in the non-diseased human heart. J Physiol 582. DOI: 10.1113/jphysiol.2006.126714. Gähwiler, B.H., and Brown, D.A. (1985). GABAB-receptor-activated K+ current in voltage-clamped CA3 pyramidal cells in hippocampal cultures. Proc Natl Acad Sci U S A 82, 1558–1562. DOI: 10.1073/pnas.82.5.1558. Glowatzki, E., Fakler, G., Brändle, U., Rexhausen, U., Zenner, H.P., Ruppersberg, J.P., and Fakler, B. (1995). Subunit-dependent assembly of inward-rectifier K+ channels. Proc Biol Sci 261, 251–261. DOI: 10.1098/rspb.1995.0145. Greger, R., Bleich, M., and Schlatter, E. (1990). Ion channels in the thick ascending limb of Henle’s loop. Ren Physiol Biochem 13, 37–50. DOI: 10.1159/000173346. Grosse, G., Eulitz, D., Thiele, T., Pahner, I., Schröter, S., Takamori, S., Grosse, J., Wickman, K., Tapp, R., Veh, R.W., Ottersen, O.P., and Ahnert-Hilger, G. (2003). Axonal sorting of Kir3.3 defines a GABA-containing neuron in the CA3 region of rodent hippocampus. Mol Cell Neurosci 24, 709–724. DOI: 10.1016/s1044-7431(03)00234-3. Hagiwara, S., and Takahashi, K. (1974). The anomalous rectification and cation selectivity of the membrane of a starfish egg cell. J Membr Biol 18, 61–80. DOI: 10.1007/BF01870103. He, C., Zhang, H., Mirshahi, T., and Logothetis, D.E. (1999). Identification of a Potassium Channel Site That Interacts with G Protein βγ Subunits to Mediate Agonist-induced Signaling*. J Biol Chem 274, 12517–12524. DOI: 10.1074/jbc.274.18.12517. He, C., Yan, X., Zhang, H., Mirshahi, T., Jin, T., Huang, A., and Logothetis, D.E. (2002). Identification of Critical Residues Controlling G Protein-gated Inwardly Rectifying K+ Channel Activity through Interactions with the βγ Subunits of G Proteins*. J Biol Chem 277, 6088–6096. DOI: 10.1074/jbc.M104851200. Hecht, M., Bromberg, Y., and Rost, B. (2015). Better prediction of functional effects for sequence variants. BMC Genomics 16 Suppl 8, S1. DOI: 10.1186/1471-2164-16-S8-S1. Heginbotham, L., Lu, Z., Abramson, T., and MacKinnon, R. (1994). Mutations in the K+ channel signature sequence. Biophys J 66, 1061–1067. Hilgemann, D.W., and Ball, R. (1996). Regulation of cardiac Na+,Ca2+ exchange and KATP potassium channels by PIP2. Science 273, 956–959. DOI: 10.1126/science.273.5277.956. Ho, I.H.M., and Murrell-Lagnado, R.D. (1999). Molecular Determinants for Sodium-dependent Activation of G Protein-gated K+ Channels*. J Biol Chem 274, 8639–8648. DOI: 10.1074/jbc.274.13.8639. Holm, H., Gudbjartsson, D.F., Sulem, P., Masson, G., Helgadottir, H.T., Zanon, C., Magnusson, O.T., Helgason, A., Saemundsdottir, J., Gylfason, A., Stefansdottir, H., Gretarsdottir, S., Matthiasson, S.E., Thorgeirsson, G.M., Jonasdottir, A., Sigurdsson, A., Stefansson, H., Werge, T., Rafnar, T., Kiemeney, L.A., Parvez, B., Muhammad, R., Roden, D.M., Darbar, D., Thorleifsson, G., et al. (2011). A rare variant in MYH6 is associated with high risk of sick sinus syndrome. Nat Genet 43, 316–320. DOI: 10.1038/ng.781. Huang, C.L., Jan, Y.N., and Jan, L.Y. (1997). Binding of the G protein betagamma subunit to multiple regions of G protein-gated inward-rectifying K+ channels. FEBS Lett 405, 291–298. DOI: 10.1016/s0014-5793(97)00197-x. Huang, C.-L., Feng, S., and Hilgemann, D.W. (1998). Direct activation of inward rectifier potassium channels by PIP2 and its stabilization by Gβγ. Nature 391, 803–806. DOI: 10.1038/35882. Ishihara, K., Yamamoto, T., and Kubo, Y. (2009). Heteromeric assembly of inward rectifier channel subunit Kir2.1 with Kir3.1 and with Kir3.4. Biochem Biophys Res Commun 380, 832–837. DOI: 10.1016/j.bbrc.2009.01.179. Iwanir, S., and Reuveny, E. (2008). Adrenaline-induced hyperpolarization of mouse pancreatic islet cells is mediated by G protein-gated inwardly rectifying potassium (GIRK) channels. Pflugers Arch 456, 1097–1108. DOI: 10.1007/s00424-008-0479-4. Jervell, A., and Lange-Nielsen, F. (1957). Congenital deaf-mutism, functional heart disease with prolongation of the Q-T interval, and sudden death. Am Heart J 54, 59–68. DOI: 10.1016/0002-8703(57)90079-0. Jiang, Y., Lee, A., Chen, J., Ruta, V., Cadene, M., Chait, B.T., and MacKinnon, R. (2003). X-ray structure of a voltage-dependent K+ channel. Nature 423, 33–41. DOI: 10.1038/nature01580. Jin, T., Peng, L., Mirshahi, T., Rohacs, T., Chan, K.W., Sanchez, R., and Logothetis, D.E. (2002). The βγ Subunits of G Proteins Gate a K+ Channel by Pivoted Bending of a Transmembrane Segment. Mol Cell 10, 469–481. DOI: 10.1016/S1097-2765(02)00659-7. John, S.A., Weiss, J.N., Xie, L.-H., and Ribalet, B. (2003). Molecular Mechanism for ATP-Dependent Closure of the K+ Channel Kir6.2. J Physiol 552, 23–34. DOI: 10.1113/jphysiol.2003.048843. Kayser, A., Dittmann, S., Šarić, T., Mearini, G., Verkerk, A.O., and Schulze-Bahr, E. (2023). The W101C KCNJ5 Mutation Induces Slower Pacing by Constitutively Active GIRK Channels in hiPSC-Derived Cardiomyocytes. Int J Mol Sci 24, 15290. DOI: 10.3390/ijms242015290. Kennedy, M.E., Nemec, J., Corey, S., Wickman, K., and Clapham, D.E. (1999). GIRK4 Confers Appropriate Processing and Cell Surface Localization to G-protein-gated Potassium Channels *. J Biol Chem 274, 2571–2582. DOI: 10.1074/jbc.274.4.2571. Kokunai, Y., Nakata, T., Furuta, M., Sakata, S., Kimura, H., Aiba, T., Yoshinaga, M., Osaki, Y., Nakamori, M., Itoh, H., Sato, T., Kubota, T., Kadota, K., Shindo, K., Mochizuki, H., Shimizu, W., Horie, M., Okamura, Y., Ohno, K., and Takahashi, M.P. (2014). A Kir3.4 mutation causes Andersen-Tawil syndrome by an inhibitory effect on Kir2.1. Neurology 82, 1058–1064. DOI: 10.1212/WNL.0000000000000239. Krapivinsky, G., Gordon, E.A., Wickman, K., Velimirović, B., Krapivinsky, L., and Clapham, D.E. (1995). The G-protein-gated atrial K+ channel IKAch is a heteromultimer of two inwardly rectifying K+-channel proteins. Nature 374, 135–141. DOI: 10.1038/374135a0. Kubo, Y., Baldwin, T.J., Jan, Y.N., and Jan, L.Y. (1993). Primary structure and functional expression of a mouse inward rectifier potassium channel. Nature 362, 127–133. DOI: 10.1038/362127a0. Kuffler, S.W., and Nicholls, J.G. (1966). The physiology of neuroglial cells. Ergeb Physiol 57, 1–90. Kuß, J., Stallmeyer, B., Goldstein, M., Rinné, S., Pees, C., Zumhagen, S., Seebohm, G., Decher, N., Pott, L., Kienitz, M.-C., and Schulze-Bahr, E. (2019). Familial Sinus Node Disease Caused by a Gain of GIRK (G-Protein Activated Inwardly Rectifying K+ Channel) Channel Function. Circ Genomic Precis Med 12, e002238. DOI: 10.1161/CIRCGEN.118.002238. Lee, S.W., Anderson, A., Guzman, P.A., Nakano, A., Tolkacheva, E.G., and Wickman, K. (2018). Atrial GIRK Channels Mediate the Effects of Vagus Nerve Stimulation on Heart Rate Dynamics and Arrhythmogenesis. Front Physiol 9. Liao, Y.J., Jan, Y.N., and Jan, L.Y. (1996). Heteromultimerization of G-protein-gated inwardly rectifying K+ channel proteins GIRK1 and GIRK2 and their altered expression in weaver brain. J Neurosci Off J Soc Neurosci 16, 7137–7150. DOI: 10.1523/JNEUROSCI.16-22-07137.1996. Liu, X., Yang, J., Shang, F., Hong, C., Guo, W., Wang, B., and Zheng, Q. (2009). Silencing GIRK4 expression in human atrial myocytes by adenovirus-delivered small hairpin RNA. Mol Biol Rep 36, 1345–1352. DOI: 10.1007/s11033-008-9318-0. Logothetis, D.E., Kurachi, Y., Galper, J., Neer, E.J., and Clapham, D.E. (1987). The beta gamma subunits of GTP-binding proteins activate the muscarinic K+ channel in heart. Nature 325, 321–326. DOI: 10.1038/325321a0. Lopatin, A.N., Makhina, E.N., and Nichols, C.G. (1994). Potassium channel block by cytoplasmic polyamines as the mechanism of intrinsic rectification. Nature 372, 366–369. DOI: 10.1038/372366a0. Ma, D., Zerangue, N., Raab-Graham, K., Fried, S.R., Jan, Y.N., and Jan, L.Y. (2002). Diverse Trafficking Patterns Due to Multiple Traffic Motifs in G Protein-Activated Inwardly Rectifying Potassium Channels from Brain and Heart. Neuron 33, 715–729. DOI: 10.1016/S0896-6273(02)00614-1. Madeira, F., Pearce, M., Tivey, A.R.N., Basutkar, P., Lee, J., Edbali, O., Madhusoodanan, N., Kolesnikov, A., and Lopez, R. (2022). Search and sequence analysis tools services from EMBL-EBI in 2022. Nucleic Acids Res 50, W276–W279. DOI: 10.1093/nar/gkac240. Makary, S.M.Y., Claydon, T.W., Dibb, K.M., and Boyett, M.R. (2006). Base of pore loop is important for rectification, activation, permeation, and block of Kir3.1/Kir3.4. Biophys J 90, 4018–4034. DOI: 10.1529/biophysj.105.073569. Matsuda, H., Saigusa, A., and Irisawa, H. (1987). Ohmic conductance through the inwardly rectifying K channel and blocking by internal Mg2+. Nature 325, 156–159. DOI: 10.1038/325156a0. Maylie, J., and Morad, M. (1984). Ionic currents responsible for the generation of pace-maker current in the rabbit sino-atrial node. J Physiol 355, 215–235. McKinney, L.C., and Gallin, E.K. (1988). Inwardly rectifying whole-cell and single-channel K currents in the murine macrophage cell line J774.1. J Membr Biol 103, 41–53. DOI: 10.1007/BF01871931. Mesirca, P., Marger, L., Toyoda, F., Rizzetto, R., Audoubert, M., Dubel, S., Torrente, A.G., DiFrancesco, M.L., Muller, J.C., Leoni, A.-L., Couette, B., Nargeot, J., Clapham, D.E., Wickman, K., and Mangoni, M.E. (2013). The G-protein–gated K+ channel, IKACh, is required for regulation of pacemaker activity and recovery of resting heart rate after sympathetic stimulation. J Gen Physiol 142, 113–126. DOI: 10.1085/jgp.201310996. Mesirca, P., Alig, J., Torrente, A.G., Müller, J.C., Marger, L., Rollin, A., Marquilly, C., Vincent, A., Dubel, S., Bidaud, I., Fernandez, A., Seniuk, A., Engeland, B., Singh, J., Miquerol, L., Ehmke, H., Eschenhagen, T., Nargeot, J., Wickman, K., Isbrandt, D., and Mangoni, M.E. (2014). Cardiac arrhythmia induced by genetic silencing of ‘funny’ (f) channels is rescued by GIRK4 inactivation. Nat Commun 5, 4664. DOI: 10.1038/ncomms5664. Monticone, S., Hattangady, N.G., Penton, D., Isales, C.M., Edwards, M.A., Williams, T.A., Sterner, C., Warth, R., Mulatero, P., and Rainey, W.E. (2013). A Novel Y152C KCNJ5 Mutation Responsible for Familial Hyperaldosteronism Type III. J Clin Endocrinol Metab 98, E1861–E1865. DOI: 10.1210/jc.2013-2428. Monticone, S., Bandulik, S., Stindl, J., Zilbermint, M., Dedov, I., Mulatero, P., Allgaeuer, M., Lee, C.-C.R., Stratakis, C.A., Williams, T.A., and Tiulpakov, A. (2015). A Case of Severe Hyperaldosteronism Caused by a De Novo Mutation Affecting a Critical Salt Bridge Kir3.4 Residue. J Clin Endocrinol Metab 100, E114–E118. DOI: 10.1210/jc.2014-3636. Neelsen, L.C., Riel, E.B., Rinné, S., Schmid, F.-R., Jürs, B.C., Bedoya, M., Langer, J.P., Eymsh, B., Kiper, A.K., Cordeiro, S., Decher, N., Baukrowitz, T., and Schewe, M. (2024). Ion occupancy of the selectivity filter controls opening of a cytoplasmic gate in the K2P channel TALK-2. Nat Commun 15, 7545. DOI: 10.1038/s41467-024-51812-w. Ng, P.C., and Henikoff, S. (2003). SIFT: Predicting amino acid changes that affect protein function. Nucleic Acids Res 31, 3812–3814. DOI: 10.1093/nar/gkg509. Nielsen, J.C., Thomsen, P.E.B., Højberg, S., Møller, M., Vesterlund, T., Dalsgaard, D., Mortensen, L.S., Nielsen, T., Asklund, M., Friis, E.V., Christensen, P.D., Simonsen, E.H., Eriksen, U.H., Jensen, G.V.H., Svendsen, J.H., Toff, W.D., Healey, J.S., Andersen, H.R., and on behalf of the DANPACE Investigators (2011). A comparison of single-lead atrial pacing with dual-chamber pacing in sick sinus syndrome. Eur Heart J 32, 686–696. DOI: 10.1093/eurheartj/ehr022. Nishida, M., and MacKinnon, R. (2002). Structural Basis of Inward Rectification: Cytoplasmic Pore of the G Protein-Gated Inward Rectifier GIRK1 at 1.8 Å Resolution. Cell 111, 957–965. DOI: 10.1016/S0092-8674(02)01227-8. Noble, D. (1965). Electrical properties of cardiac muscle attributable to inward going (anomalous) rectification. J Cell Comp Physiol 66, 127–135. DOI: 10.1002/jcp.1030660520. Noma, A., and Irisawa, H. (1976). Membrane currents in the rabbit sinoatrial node cell as studied by the double microelectrode method. Pflugers Arch 364, 45–52. DOI: 10.1007/BF01062910. Pegan, S., Arrabit, C., Zhou, W., Kwiatkowski, W., Collins, A., Slesinger, P.A., and Choe, S. (2005). Cytoplasmic domain structures of Kir2.1 and Kir3.1 show sites for modulating gating and rectification. Nat Neurosci 8, 279–287. DOI: 10.1038/nn1411. Petit-Jacques, J., Sui, J.L., and Logothetis, D.E. (1999). Synergistic Activation of G Protein–Gated Inwardly Rectifying Potassium Channels by the βγ Subunits of G Proteins and Na+ and Mg2+ Ions. J Gen Physiol 114, 673–684. DOI: 10.1085/jgp.114.5.673. Piechotta, P.L., Rapedius, M., Stansfeld, P.J., Bollepalli, M.K., Erhlich, G., Andres-Enguix, I., Fritzenschaft, H., Decher, N., Sansom, M.S.P., Tucker, S.J., and Baukrowitz, T. (2011). The pore structure and gating mechanism of K2P channels. EMBO J 30, 3607–3619. DOI: 10.1038/emboj.2011.268. Rödström, K.E.J., Kiper, A.K., Zhang, W., Rinné, S., Pike, A.C.W., Goldstein, M., Conrad, L.J., Delbeck, M., Hahn, M.G., Meier, H., Platzk, M., Quigley, A., Speedman, D., Shrestha, L., Mukhopadhyay, S.M.M., Burgess-Brown, N.A., Tucker, S.J., Müller, T., Decher, N., and Carpenter, E.P. (2020). A lower X-gate in TASK channels traps inhibitors within the vestibule. Nature 582, 443–447. DOI: 10.1038/s41586-020-2250-8. Rosenhouse-Dantsker, A., Sui, J.L., Zhao, Q., Rusinova, R., Rodríguez-Menchaca, A.A., Zhang, Z., and Logothetis, D.E. (2008). A sodium-mediated structural switch that controls the sensitivity of Kir channels to PtdIns(4,5)P2. Nat Chem Biol 4, 624–631. DOI: 10.1038/nchembio.112. Sakmann, B., and Trube, G. (1984). Conductance properties of single inwardly rectifying potassium channels in ventricular cells from guinea-pig heart. J Physiol 347, 641–657. Sakmann, B., Noma, A., and Trautwein, W. (1983). Acetylcholine activation of single muscarinic K+ channels in isolated pacemaker cells of the mammalian heart. Nature 303, 250–253. DOI: 10.1038/303250a0. Sanguinetti, and Jurkiewicz (1990). Two components of cardiac delayed rectifier K+ current. Differential sensitivity to block by class III antiarrhythmic agents. J Gen Physiol 96. DOI: 10.1085/jgp.96.1.195. Schewe, M., Nematian-Ardestani, E., Sun, H., Musinszki, M., Cordeiro, S., Bucci, G., de Groot, B.L., Tucker, S.J., Rapedius, M., and Baukrowitz, T. (2016). A Non-canonical Voltage-Sensing Mechanism Controls Gating in K2P K(+) Channels. Cell 164, 937–949. DOI: 10.1016/j.cell.2016.02.002. Scholl, U.I., Nelson-Williams, C., Yue, P., Grekin, R., Wyatt, R.J., Dillon, M.J., Couch, R., Hammer, L.K., Harley, F.L., Farhi, A., Wang, W.-H., and Lifton, R.P. (2012). Hypertension with or without adrenal hyperplasia due to different inherited mutations in the potassium channel KCNJ5. Proc Natl Acad Sci 109, 2533–2538. DOI: 10.1073/pnas.1121407109. Silver, M.R., and DeCoursey, T.E. (1990). Intrinsic gating of inward rectifier in bovine pulmonary artery endothelial cells in the presence or absence of internal Mg2+. J Gen Physiol 96, 109–133. DOI: 10.1085/jgp.96.1.109. Sims, S.M., and Dixon, S.J. (1989). Inwardly rectifying K+ current in osteoclasts. Am J Physiol-Cell Physiol 256, C1277–C1282. DOI: 10.1152/ajpcell.1989.256.6.C1277. Stallmeyer, B., Kuß, J., Kotthoff, S., Zumhagen, S., Vowinkel, K., Rinné, S., Matschke, L.A., Friedrich, C., Schulze-Bahr, E., Rust, S., Seebohm, G., Decher, N., and Schulze-Bahr, E. (2017). A Mutation in the G-Protein Gene GNB2 Causes Familial Sinus Node and Atrioventricular Conduction Dysfunction. Circ Res 120, e33–e44. DOI: 10.1161/CIRCRESAHA.116.310112. Stanfield, P.R., Davies, N.W., Shelton, P.A., Sutcliffe, M.J., Khan, I.A., Brammar, W.J., and Conley, E.C. (1994). A single aspartate residue is involved in both intrinsic gating and blockage by Mg2+ of the inward rectifier, IRK1. J Physiol 478, 1–6. DOI: 10.1113/jphysiol.1994.sp020225. Swartz, K.J. (2008). Sensing voltage across lipid membranes. Nature 456, 891–897. DOI: 10.1038/nature07620. Tauber, P., Penton, D., Stindl, J., Humberg, E., Tegtmeier, I., Sterner, C., Beuschlein, F., Reincke, M., Barhanin, J., Bandulik, S., and Warth, R. (2014). Pharmacology and Pathophysiology of Mutated KCNJ5 Found in Adrenal Aldosterone-Producing Adenomas. Endocrinology 155, 1353–1362. DOI: 10.1210/en.2013-1944. The UniProt Consortium (2025). UniProt: the Universal Protein Knowledgebase in 2025. Nucleic Acids Res 53, D609–D617. DOI: 10.1093/nar/gkae1010. Wang, F., Liu, J., Hong, L., Liang, B., Graff, C., Yang, Y., Christiansen, M., Olesen, S.-P., Zhang, L., and Kanters, J.K. (2013). The phenotype characteristics of type 13 long QT syndrome with mutation in KCNJ5 (Kir3.4-G387R). Heart Rhythm 10, 1500–1506. DOI: 10.1016/j.hrthm.2013.07.022. Whorton, M.R., and MacKinnon, R. (2013). X-ray structure of the mammalian GIRK2 – βγ G protein complex. Nature 498, 190–197. DOI: 10.1038/nature12241. Wickman, K., Nemec, J., Gendler, S.J., and Clapham, D.E. (1998). Abnormal Heart Rate Regulation in GIRK4 Knockout Mice. Neuron 20, 103–114. DOI: 10.1016/S0896-6273(00)80438-9. Wickman, K., Karschin, C., Karschin, A., Picciotto, M.R., and Clapham, D.E. (2000). Brain localization and behavioral impact of the G-protein-gated K+ channel subunit GIRK4. J Neurosci Off J Soc Neurosci 20, 5608–5615. DOI: 10.1523/JNEUROSCI.20-15-05608.2000. Woodward, R., Stevens, E.B., and Murrell-Lagnado, R.D. (1997). Molecular Determinants for Assembly of G-protein-activated Inwardly Rectifying K+ Channels*. J Biol Chem 272, 10823–10830. DOI: 10.1074/jbc.272.16.10823. Yamada, N., Asano, Y., Fujita, M., Yamazaki, S., Inanobe, A., Matsuura, N., Kobayashi, H., Ohno, S., Ebana, Y., Tsukamoto, O., Ishino, S., Takuwa, A., Kioka, H., Yamashita, T., Hashimoto, N., Zankov, D.P., Shimizu, A., Asakura, M., Asanuma, H., Kato, H., Nishida, Y., Miyashita, Y., Shinomiya, H., Naiki, N., Hayashi, K., et al. (2019). Mutant KCNJ3 and KCNJ5 Potassium Channels as Novel Molecular Targets in Bradyarrhythmias and Atrial Fibrillation. Circulation 139, 2157–2169. DOI: 10.1161/CIRCULATIONAHA.118.036761. Yang, Y., Yang, Y., Liang, B., Liu, J., Li, J., Grunnet, M., Olesen, S.-P., Rasmussen, H.B., Ellinor, P.T., Gao, L., Lin, X., Li, L., Wang, L., Xiao, J., Liu, Y., Liu, Y., Zhang, S., Liang, D., Peng, L., Jespersen, T., and Chen, Y.-H. (2010). Identification of a Kir3.4 mutation in congenital long QT syndrome. Am J Hum Genet 86, 872–880. DOI: 10.1016/j.ajhg.2010.04.017. Yoshimoto, Y., Fukuyama, Y., Horio, Y., Inanobe, A., Gotoh, M., and Kurachi, Y. (1999). Somatostatin induces hyperpolarization in pancreatic islet α cells by activating a G protein-gated K+ channel. FEBS Lett 444, 265–269. DOI: 10.1016/S0014-5793(99)00076-9. Zhang, H., He, C., Yan, X., Mirshahi, T., and Logothetis, D.E. (1999). Activation of inwardly rectifying K+ channels by distinct PtdIns(4,5)P2 interactions. Nat Cell Biol 1, 183–188. DOI: 10.1038/11103.
Faculty
FB20:Medizin
Language
de
Keywords
Kir3.4 GIRK4 LQT-Syndrom SSS SND
DFG-subjects
2.22-04 - Anatomie und Physiologie2.22-12 - Kardiologie, Angiologie
show more
License
Except where otherwise noted, this item's license is described as Attribution 4.0 International