The intriguing effect of ethanol and nicotine on acetylcholine-sensitive potassium current IKAch: Insight from a quantitative model


Autoři: Jiří Šimurda aff001;  Milena Šimurdová aff001;  Markéta Bébarová aff001
Působiště autorů: Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice, Brno, Czech Republic aff001
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: 10.1371/journal.pone.0223448

Souhrn

Recent experimental work has revealed unusual features of the effect of certain drugs on cardiac inwardly rectifying potassium currents, including the constitutively active and acetylcholine-induced components of acetylcholine-sensitive current (IKAch). These unusual features have included alternating susceptibility of the current components to activation and inhibition induced by ethanol or nicotine applied at various concentrations, and significant correlation between the drug effect and the current magnitude measured under drug-free conditions. To explain these complex drug effects, we have developed a new type of quantitative model to offer a possible interpretation of the effect of ethanol and nicotine on the IKAch channels. The model is based on a description of IKAch as a sum of particular currents related to the populations of channels formed by identical assemblies of different α-subunits. Assuming two different channel populations in agreement with the two reported functional IKAch-channels (GIRK1/4 and GIRK4), the model was able to simulate all the above-mentioned characteristic features of drug-channel interactions and also the dispersion of the current measured in different cells. The formulation of our model equations allows the model to be incorporated easily into the existing integrative models of electrical activity of cardiac cells involving quantitative description of IKAch. We suppose that the model could also help make sense of certain observations related to the channels that do not show inward rectification. This new ionic channel model, based on a concept we call population type, may allow for the interpretation of complex interactions of drugs with ionic channels of various types, which cannot be done using the ionic channel models available so far.

Klíčová slova:

Acetylcholine – Alcohols – Drug interactions – Ethanol – Membrane potential – Nicotine – Potassium channels – Simulation and modeling


Zdroje

1. Bébarová M, Matejovič P, Pásek M, Šimurdová M, Šimurda J. Dual effect of ethanol on inward rectifier potassium current IK1 in rat ventricular myocytes. J Physiol Pharmacol. 2014;65: 497–502. 25179082

2. Hořáková Z, Matejovič P, Pásek M, Hošek J, Šimurdová M, Šimurda J. Effect of ethanol and acetaldehyde at clinically relevant concentrations on atrial inward rectifier potassium current IK1: separate and combine effect. J Physiol Pharmacol. 2016;67: 339–351. 27511995

3. Bébarová M, Matejovič P, Pásek M, Hořáková Z, Hošek J, Šimurdová M, et al. Effect of ethanol at clinically relevant concentrations on atrial inward rectifier potassium current sensitive to acetylcholine. Naunyn-Schmiedeberg´s Arch Pharmacol. 2016;389: 1049–1058.

4. Bébarová M, Matejovič P, Švecová O, Kula R, Šimurdová M, Šimurda J. Nicotine at clinically relevant concentrations affects atrial inward rectifier potassium current sensitive to acetylcholine. Naunyn-Schmiedeberg´s Arch Pharmacol. 2017;390: 471–481.

5. Weigl LG, Schreibmayer WG. Protein-gated inwardly rectifying potassium channels are targets for volatile anesthetics. Mol Pharmacol. 2001;60: 282–289. doi: 10.1124/mol.60.2.282 11455015

6. Milovic S, Steinecker-Frohnwieser B, Schreibmayer W, Weigl LG. The sensitivity of G protein-activated K+ channels toward halothane is essentially determined by the C terminus. J Biol Chem. 2004;279: 34240–34249. doi: 10.1074/jbc.M403448200 15175324

7. Dhamoon AS, Pandit SV, Sarmast F, Parisian KR, Guha P, Li Y, et al. Unique Kir2.x properties determine regional and species differences in the cardiac inward rectifier K+ current. Circ Res. 2004;94: 1332–1339. doi: 10.1161/01.RES.0000128408.66946.67 15087421

8. Ehrlich JR. Inward rectifier potassium currents as a target for atrial fibrillation therapy. J Cardiovasc Pharmacol. 2008;52: 129–135. doi: 10.1097/FJC.0b013e31816c4325 18670367

9. Hibino H, Inanobe A, Furutani K, Murakami S, Findlay I, Kurachi Y. Inwardly rectifying potassium channels: their structure, function, and physiological roles. Physiol Rev. 2010;90: 291–366. doi: 10.1152/physrev.00021.2009 20086079

10. Šimurda J, Šimurdová M, Bébarová M. Inward rectifying potassium currents resolved into components: modeling of complex actions. Pflugers Arch–Eur J Physiol. 2018;470: 315–325.

11. Krapivinsky G, Gordon EA, Wickman K, Velimirovic B, Krapivinsky L, Clapham DE. The G-protein-gated atrial K+ channel IKACh is a heteromultimer of two inwardly rectifying K+-channel proteins. Nature. 1995;374: 135–141. doi: 10.1038/374135a0 7877685

12. Corey S, Krapivinsky G, Krapivinsky L, Clapham DE. Number and stoichiometry of subunits in the native atrial G-protein-gated K+ channel, IKACh. J Biol Chem. 1998;273: 5271–5278. doi: 10.1074/jbc.273.9.5271 9478984

13. Corey S, Clapham DE. Identification of native atrial G-protein-regulated inwardly rectifying K+ (GIRK4) channel homomultimers. J Biol Chem. 1998;273: 27499–27504. 9765280

14. Kennedy ME, Nemec J, Corey S, Wickman K, Clapham DE. GIRK4 confers appropriate processing and cell surface localization to G-protein-gated potassium channels. J Biol Chem. 1999;274: 2571–2582. doi: 10.1074/jbc.274.4.2571 9891030

15. Bender K, Wellner-Kienitz MC, Inanobe A, Meyer T, Kurachi Y, Pott L. Overexpression of monomeric and multimeric GIRK4 subunits in rat atrial myocytes removes fast desensitization and reduces inward rectification of muscarinic K+current (IK(ACh)). Evidence for functional homomeric GIRK4 channels. J Biol Chem. 2001; 276: 28873–28880. doi: 10.1074/jbc.M102328200 11384974

16. Touhara KK, Wang W, MacKinnon R (2016) The GIRK1 subunit potentiates G protein activation of cardiac GIRK1/4 hetero-tetramers. eLife;5:e15750. doi: 10.7554/eLife.15750 27074664

17. Mirshahi T, Logothetis DE. Molecular determinants responsible for differential cellular distribution of G protein-gated inwardly rectifying K+ channels. J Biol Chem. 2004;279: 11890–11897. 14703518

18. Inanobe A, Kurachi Y. Membrane channels as integrators of G-protein-mediated signaling. Biochim Biophys Acta. 2014;1838: 521–531. doi: 10.1016/j.bbamem.2013.08.018 24028827

19. Lewohl JM, Wilson WR, Mayfield RD, Brozowski SJ, Morrisett RA, Harris RA. Gprotein coupled inwardly rectifying potassium channels are targets of alcohol action. Nat Neurosci. 1999;2: 1084–1090. doi: 10.1038/16012 10570485

20. Aryal P, Dvir H, Choe S, Slesinger PA. A discrete alcohol pocket involved in GIRK channel activation. Nat Neurosci. 2009;12: 988–995. doi: 10.1038/nn.2358 19561601

21. Mahajan R, Ha J, Zhang M, Kawano T, Kozasa T, Logothetis DE. Computational model predicts that Gβγ acts at a cleft between channel subunits to activate GIRK1 channels. Sci Signal. 2013;6:ra69. doi: 10.1126/scisignal.2004075 23943609

22. Toyama Y, Kano H, Mase Y, Yokogawa M, Osawa M, Shimada I. Structural basis for the ethanol action on G-protein–activated inwardly rectifying potassium hannel 1 revealed by NMR spectroscopy. PNAS. 2018;115: 3858–3863. doi: 10.1073/pnas.1722257115 29581303

23. Bodhinathan K, Slesinger PA. Molecular mechanism underlying ethanol activation of G-protein-gated inwardly rectifying potassium channels. Proc Natl Acad Sci USA. 2013;110: 18309–18314. doi: 10.1073/pnas.1311406110 24145411

24. Treiber F, Rosker C, Keren-Raifman T, Steinecker B, Gorischek A, Dascal N, et al. Molecular basis of the facilitation of the heterooligomeric GIRK1/GIRK4 complex by cAMP dependent protein kinase. Biochim Biophys Acta. 2013;1828: 1214–1221. doi: 10.1016/j.bbamem.2012.12.016 23305758

25. Li J, Lü S, Liu Y, Pang C, Chen Y, S Zhang, et al. Identification of the conformational transition pathway in PIP2 opening Kir channels. Sci Rep. 2015;5: 11289. doi: 10.1038/srep11289 26063437

26. Christé G, Tebbakh H, Šimurdová M, Forrat R, Šimurda J. Propafenone blocks ATP-sensitive K+ channels in rabbit atrial and ventricular cardiomyocytes. Eur J Pharmacol. 1999;373: 223–232. doi: 10.1016/s0014-2999(99)00217-4 10414443

27. Kobayashi T, Washiyama K, Ikeda K. Inhibition of G protein-activated inwardly rectifying K+ channels by various antidepressant drugs. Neuropsychopharmacology. 2004;29: 1841–1851. doi: 10.1038/sj.npp.1300484 15150531

28. Kobayashi T, Washiyama K, Ikeda K. Inhibition of G protein-activated inwardly rectifying K+ channels by ifenprodil. Neuropsychopharmacology. 2006;31: 516–524. doi: 10.1038/sj.npp.1300844 16123769

29. Caballero R, Dolz-Gaitón P, Gómez R, Amorós I, Barana A, González de la Fuente M, et al. Flecainide increases Kir2.1 currents by interacting with cysteine 311, decreasing the polyamine-induced rectification. PNAS. 2010;107: 15631–15636. doi: 10.1073/pnas.1004021107 20713726

30. Walsh KB. A real-time screening assay for GIRK1/4 channel blockers. J Biomol Screen. 2010;15: 1229–1237. doi: 10.1177/1087057110381384 20938046

31. Ferrer T, Ponce-Balbuena D, López-Izquierdo A, Aréchiga-Figueroa IA, de Boer TP, van der Heyden MAG, et al. Carvedilol inhibits Kir2.3 channels by interference with PIP2-channel interaction. Eur J Pharmacol. 2011;668: 72–77. doi: 10.1016/j.ejphar.2011.05.067 21663737

32. Liu QH, Li XL, Xu YW, Lin YY, Cao JM, Wu BW. A novel discovery of IK1 channel agonist: zacopride selectively enhances IK1 current and suppresses triggered arrhythmias in the rat. J Cardiovasc Pharmacol. 2012;59: 37–48. doi: 10.1097/FJC.0b013e3182350bcc 21921806

33. Vanheiden S, Pott L, Kienitz MC. Voltage-dependent open-channel block of G protein-gated inward-rectifying K+ (GIRK) current in rat atrial myocytes by tamoxifen. Naunyn-Schmiedeberg's Arch Pharmacol. 2012;385: 1149–1160.

34. Gómez R, Caballero R, Barana A, Amorós I, DePalm SH, Matamoros M, et al. Structural basis of drugs that increase cardiac inward rectifier Kir2.1 currents. Cardiovasc Res. 2014;104: 337–346. doi: 10.1093/cvr/cvu203 25205296

35. Kobayashi T, Ikeda K, Kojima H, Niki H, Yano R, Yoshioka T, et al. Ethanol opens G-protein-activated inwardly rectifying K+ channels. Nat Neurosci. 1999;2: 1091–1097. doi: 10.1038/16019 10570486

36. Yamakura T, Lewohl JM, Harris RA. Differential effects of general anesthetics on G protein–coupled inwardly rectifying and other potassium channels. Anesthesiology. 2001;95: 144–153. doi: 10.1097/00000542-200107000-00025 11465552

37. Bébarová M, Matejovič P, Pásek M, Ohlídalová D, Jansová D, Šimurdová M, et al. Effect of ethanol on action potential and ionic membrane currents in rat ventricular myocytes. Acta Physiol (Oxf). 2010;200: 301–314.

38. Zuo Y, Aistrup GL, Marszalec W, Gillespie A, Chavez-Noriega LE, Yeh JZ, et al. Dual action of n-alcohols on neuronal nicotinic acetylcholine receptors. J Mol Pharmacol. 2001;6: 700–711.

39. Borghese CM, Henderson LA, Bleck V, Trudell JR, Harris RA. Sites of excitatory and inhibitory actions of alcohols on neuronal α2 β4 nicotinic acetylcholine receptors. J Pharmacol Exper Ther. 2003;307: 42–52.

40. Murail S, Howard RJ, Broemstrup T, Bertaccini EJ, Harris RA, Trudell JR, et al. Molecular mechanism for the dual alcohol modulation of cys-loop receptors. PloS Comput Biol. 2012;8: e1002710. doi: 10.1371/journal.pcbi.1002710 23055913

41. Zhou W, Arrabit C, Choe S, Slesinger PA. Mechanism underlying bupivacaine inhibition of G protein-gated inwardly rectifying K+ channels. PNAS. 2001;98:6482–6487. doi: 10.1073/pnas.111447798 11353868

42. Huang CL, Feng S, Hilgemann DW. Direct activation of inward rectifier potassium channels by PIP2 and its stabilization by Gβγ. Nature. 1998;391: 803–806. doi: 10.1038/35882 9486652

43. Zhang H, He C, Yan X, Mirshahi T, Logothetis DE. Activation of inwardly rectifying K+ channels by distinct PtdIns(4,5)P2 interactions. Nat Cell Biol. 1999;1: 183–188. doi: 10.1038/11103 10559906

44. Xie LH, John SA, Ribalet B, Weiss JN. Activation of inwardly rectifying potassium (Kir) channels by phosphatidylinosital-4,5-bisphosphate (PIP2): interaction with other regulatory ligands. Prog Biophys Mol Biol. 2007;94: 320–335. doi: 10.1016/j.pbiomolbio.2006.04.001 16837026

45. Lacin E, Aryal P Glaaser IW, Bodhinathan K, Tsai E, Marsh N, et al. Dynamic role of the tether helix in PIP2-dependent gating of a G protein–gated potassium channel. J Gen Physiol. 2017 Jul 18. pii: jgp.201711801. doi: 10.1085/jgp.201711801 28720589

46. Logothetis DE, Jin T, Lupyan D, Rosenhouse-Dantsker A. Phosphoinositidemediated gating of inwardly rectifying K+ channels. Pflugers Arch—Eur J Physiol. 2007;455: 83–95.


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