Advertisement

Pflügers Archiv - European Journal of Physiology

, Volume 470, Issue 2, pp 315–325 | Cite as

Inward rectifying potassium currents resolved into components: modeling of complex drug actions

  • Jiří Šimurda
  • Milena Šimurdová
  • Markéta BébarováEmail author
Ion channels, receptors and transporters
  • 154 Downloads
Part of the following topical collections:
  1. Ion channels, receptors and transporters

Abstract

Inward rectifier potassium currents (I Kir,x) belong to prominent ionic currents affecting both resting membrane voltage and action potential repolarization in cardiomyocytes. In existing integrative models of electrical activity of cardiac cells, they have been described as single current components. The proposed quantitative model complies with findings indicating that these channels are formed by various homomeric or heteromeric assemblies of channel subunits with specific functional properties. Each I Kir,x may be expressed as a total of independent currents via individual populations of identical channels, i.e., channels formed by the same combination of their subunits. Solution of the model equations simulated well recently observed unique manifestations of dual ethanol effect in rat ventricular and atrial cells. The model reflects reported occurrence of at least two binding sites for ethanol within I Kir,x channels related to slow allosteric conformation changes governing channel conductance and inducing current activation or inhibition. Our new model may considerably improve the existing models of cardiac cells by including the model equations proposed here in the particular case of the voltage-independent drug-channel interaction. Such improved integrative models may provide more precise and, thus, more physiologically relevant results.

Keywords

Quantitative model Cardiomyocytes Inward rectifier potassium currents IK1 Ethanol Dual effect 

Abbreviations

c

Drug concentration

fj

Fraction of j th channel population

f1

Fraction of channels showing activation

f2, f3

Fractions of channels showing inhibition

GKir,x

Total conductance of I Kir,x channel

GKir,x,j, Gj

Conductance of the jth channel population

Gss,j

Steady-state conductance of the jth channel population

G0,jG1,j, G2,j

Steady-state conductance of the jth channel population related to sets of vacant channels, channels occupied by one or two drug molecules, respectively

IKir, IKir,x

Inward rectifier potassium current (generally)

IKir,x,j, Ij

Current through jth channel population

IK1, IKAch, IKATP

Inward rectifier potassium currents

IK1,j

I K1 through jth channel population

INa, ICa, Ito

Sodium, calcium, and transient outward potassium currents

j

Individual populations of identical channels (j = 1,…,n)

[K+]e

Extracellular concentration of potassium ions

Kir2.x

Molecular identities of I K1 channels (Kir2.1, Kir2.2, Kir2.3)

Kir3.x

Molecular identities of I KAch channels (Kir3.1, Kir3.4)

Kir6.x/SURx

Molecular identities of I KATP channels

K1,j, K2,j

Binding constants (binding of the first and the second molecule, respectively)

n

Number of different populations

PIP2

Phospholipid phosphatidylinositol-4,5-bisphosphate

τj

Time constants related to jth channel population

U

Membrane voltage

UK

Equilibrium voltage of potassium ions

x0,j, x1,j, x2,j

Probability of channels (pertaining to jth channel population) to be found drug free, occupied by one, or by two drug molecules, respectively

Notes

Acknowledgments

The authors wish to thank Prof. P. Bravený for reading the manuscript and valuable comments.

Funding

This study was supported by Ministry of Health of the Czech Republic, grant nr. 16-30571A.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    An HL, Lü SQ, Li JW, Meng XY, Zhan Y, Cui M, Long M, Zhang HL, Logothetis DE (2012) The cytosolic GH loop regulates the phosphatidylinositol 4,5-bisphosphate-induced gating kinetics of gating kinetics of Kir2 channels. J Biol Chem 287:42278–42287.  https://doi.org/10.1074/jbc.M112.418640 CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Aryal P, Dvir H, Choe S, Slesinger PA (2009) A discrete alcohol pocket involved in GIRK channel activation. Nat Neuroscin 12:988–995.  https://doi.org/10.1038/nn.2358 CrossRefGoogle Scholar
  3. 3.
    Bébarová M, Matejovič P, Pásek M, Ohlídalová D, Jansová D, Šimurdová M, Šimurda J (2010) Effect of ethanol on action potential and ionic membrane currents in rat ventricular myocytes. Acta Physiol (Oxf) 200:301–314.  https://doi.org/10.1111/j.1748-1716.2010.02162.x CrossRefGoogle Scholar
  4. 4.
    Bébarová M, Matejovič P, Pásek M, Šimurdová M, Šimurda J (2014) Dual effect of ethanol on inward rectifier potassium current I K1 in rat ventricular myocytes. J Physiol Pharmacol 65:497–502PubMedGoogle Scholar
  5. 5.
    Bébarová M, Matejovič P, Pásek M, Hořáková Z, Hošek J, Šimurdová M, Šimurda J (2016) Effect of ethanol at clinically relevant concentrations on atrial inward rectifier potassium current sensitive to acetylcholine. Naunyn-Schmiedeberg’s Arch Pharmacol 389:1049–1058.  https://doi.org/10.1007/s00210-016-1265-z CrossRefGoogle Scholar
  6. 6.
    Bernus O, Wilders R, Zemlin CW, Verschelde H, Panfilov AV (2002) A computationally efficient electrophysiological model of human ventricular cells. Am J Physiol Heart Circ Physiol 282:H2296–H2308.  https://doi.org/10.1152/ajpheart.00731.2001 CrossRefPubMedGoogle Scholar
  7. 7.
    Bodhinathan K, Slesinger PA (2013) Molecular mechanism underlying ethanol activation of G-protein-gated inwardly rectifying potassium channels. Proc Natl Acad Sci U S A 110:18309–18314.  https://doi.org/10.1073/pnas.1311406110 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Bondarenko VE, Szigeti GP, Bett GCL, Kim SJ, Rasmusson RL (2004) Computer model of action potential of mouse ventricular myocytes. Am J Physiol Heart Circ Physiol 287:H1378–H1403.  https://doi.org/10.1152/ajpheart.00185.2003 CrossRefPubMedGoogle Scholar
  9. 9.
    Borghese CM, Henderson LA, Bleck V, Trudell JR, Harris RA (2003) Sites of excitatory and inhibitory actions of alcohols on neuronal α2 β4 nicotinic acetylcholine receptors. J Pharmacol Exper Ther 307:42–52.  https://doi.org/10.1124/jpet.103.053710 CrossRefGoogle Scholar
  10. 10.
    Caballero R, Dolz-Gaitón P, Gómez R, Amorós I, Barana A et al (2010) Flecainide increases Kir2.1 currents by interacting with cysteine 311, decreasing the polyamide induced rectification. PNAS 107:15631–15636.  https://doi.org/10.1073/pnas.1004021107 CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Calabrese EJ (2008) Hormesis and medicine. Brit J Clin Pharmacol 66:594–617.  https://doi.org/10.1111/j.1365-2125.2008.03243.x Google Scholar
  12. 12.
    Dhamoon AS, Pandit SV, Sarmast F, Parisian KR, Guha P, Li Y, Bagwe S, Taffet SM, Anumonwo JM (2004) Unique Kir2.x properties determine regional and species differences in the cardiac inward rectifier K+ current. Circ Res 94:1332–1339.  https://doi.org/10.1161/​01.RES.0000128408.66946.67 CrossRefPubMedGoogle Scholar
  13. 13.
    Ehrlich JR (2008) Inward rectifier potassium currents as a target for atrial fibrillation therapy. J Cardiovasc Pharmacol 52:129–135.  https://doi.org/10.1097/FJC.0b013e31816c4325 CrossRefPubMedGoogle Scholar
  14. 14.
    Ferrer T, Ponce-Balbuena D, López-Izquierdo A, Aréchiga-Figueroa IA, de Boer TP, van der Heyden MAG, Sánchez-Chapula JA (2011) Carvedilol inhibits Kir2.3 channels by interference with PIP2-channel interaction. Eur J Pharmacol 668:72–77.  https://doi.org/10.1016/j.ejphar.2011.05.067 CrossRefPubMedGoogle Scholar
  15. 15.
    Fink M, Noble D, Virag L, Varro A, Giles WR (2008) Contributions of HERG K+ current to repolarization of the human ventricular action potential. Prog Biophys Mol Biol 96:357–376.  https://doi.org/10.1016/j.pbiomolbio.2007.07.011 CrossRefPubMedGoogle Scholar
  16. 16.
    Gaborit N, Le Bouter S, Szuts V, Varro A, Escande D, Nattel S, Demolombe S (2007) Regional and tissue specific transcript signatures of ion channel genes in the non-diseased human heart. J Physiol 582:675–693.  https://doi.org/10.1113/jphysiol.2006.126714 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Gómez R, Caballero R, Barana A, Amorós I, DePalm SH, Matamoros M, Núñez M, Pérez-Hernández M, Iriepa I, Tamargo J, Delpón E (2014) Structural basis of drugs that increase cardiac inward rectifier Kir2.1 currents. Cardiovasc Res 104:337–346.  https://doi.org/10.1093/cvr/cvu203 CrossRefPubMedGoogle Scholar
  18. 18.
    Hansen SB, Tao X, MacKinnon R (2011) Structural basis of PIP2 activation of the classical inward rectifier K+ channel Kir2.2. Nature 477:495–498.  https://doi.org/10.1038/nature10370 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Hibino H, Inanobe A, Furutani K, Murakami S, Findlay I, Kurachi Y (2010) Inwardly rectifying potassium channels: their structure, function, and physiological roles. Physiol Rev 90:291–366.  https://doi.org/10.1152/physrev.00021.2009 CrossRefPubMedGoogle Scholar
  20. 20.
    Hořáková Z, Matejovič P, Pásek M, Hošek J, Šimurdová M, Šimurda J (2016) Effect of ethanol and acetaldehyde at clinically relevant concentrations on atrial inward rectifier potassium current I K1: separate and combine effect. J Physiol Pharmacol 67:339–351PubMedGoogle Scholar
  21. 21.
    Hrabcová D, Pásek M, Šimurda J, Christé G (2013) Effect of ion concentration changes in the limited extracellular spaces on sarcolemmal ion transport and Ca2+ turnover in a model of human ventricular cardiomyocyte. Int J Mol Sci 14:24271–24292.  https://doi.org/10.3390/ijms141224271 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Iyer V, Mazhari R, Winslow RL (2004) A computational model of the human left-ventricular epicardial myocyte. Biophys J 87:1507–1525.  https://doi.org/10.1529/biophysj.104.043299 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Liu GX, Derst C, Schlichthorl G, Heinen S, Seebohm G, Bruggemann A, Kummer W, Veh RW, Daut J, Preisig-Muller R (2001) Comparison of cloned Kir2 channels with native inward rectifier K+ channels from guinea-pig cardiomyocytes. J Physiol 532:115–126.  https://doi.org/10.1111/j.1469-7793.2001.0115g.x CrossRefPubMedGoogle Scholar
  24. 24.
    Liu QH, Li XL, Xu YW, Lin YY, Cao JM, Wu BW (2012) A novel discovery of I K1 channel agonist: zacopride selectively enhances I K1 current and suppresses triggered arrhythmias in the rat. J Cardiovasc Pharmacol 59:37–48.  https://doi.org/10.1097/FJC.0b013e3182350bcc CrossRefPubMedGoogle Scholar
  25. 25.
    López-Izquierdo A, Aréchiga-Figueroa IA, Moreno-Galindo EG, Ponce-Balbuena DM, Ferrer-Villada T, Rodríguez-Menchaca AA, van der Heyden MAG, Sánchez-Chapula JA (2011) Mechanisms for Kir channel inhibition by quinacrine: acute pore block of Kir2.x channels and interference in PIP2 interaction with Kir2.x and Kir6.2 channels. Pflugers Arch 462:505–517.  https://doi.org/10.1007/s00424-011-0995-5 CrossRefPubMedGoogle Scholar
  26. 26.
    Murail S, Howard RJ, Broemstrup T, Bertaccini EJ, Harris RA, Trudell JR, Lindahl E (2012) Molecular mechanism for the dual alcohol modulation of cys-loop receptors. PLoS Comput Biol 8:e1002710.  https://doi.org/10.1371/journal.pcbi.1002710 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Noujaim SF, Stuckey JA, Ponce-Balbuena D, Ferrer-Villada T, López-Izquierdo A, Pandit SV, Sánchez-Chapula JA, Jalife J (2011) Structural bases for the different anti-fibrillatory effects of chloroquine and quinidine. Cardiovasc Res 89:1–8.  https://doi.org/10.1093/cvr/cvr008 CrossRefGoogle Scholar
  28. 28.
    Nishida M, Cadene M, Chait BT, MacKinnon R (2007) Crystal structure of a Kir3.1-prokaryotic Kir channel chimera. EMBO J 26:4005–4015.  https://doi.org/10.1038/sj.emboj.7601828 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    O’Hara T, László V, Varró A, Rudy Y (2011) Simulation of the undiseased human cardiac ventricular action potential: model formulation and experimental validation. PLoS Comput Biol 7:e1002061.  https://doi.org/10.1371/journal.pcbi.1002061 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Pásek M, Šimurda J, Orchard CH, Christé G (2008) A model of the guinea-pig ventricular cardiomyocyte incorporating a transverse-axial tubular system. Prog Biophys Mol Biol 96:258–280.  https://doi.org/10.1016/j.pbiomolbio.2007.07.022 CrossRefPubMedGoogle Scholar
  31. 31.
    Pásek M, Šimurda J, Orchard CH (2012) Role of t-tubules in the control of trans-sarcolemmal ion flux and intracellular Ca2+ in a model of the rat cardiac ventricular myocyte. Eur Biophys J 41:491–503.  https://doi.org/10.1007/s00249-012-0804-x CrossRefPubMedGoogle Scholar
  32. 32.
    Pegan S, Arrabit C, Slesinger PA, Choe S (2006) Andersen’s syndrome mutation effects on the structure and assembly of the cytoplasmic domains of Kir2.1. Biochemistry 45:8599–8606.  https://doi.org/10.1021/bi060653d CrossRefPubMedGoogle Scholar
  33. 33.
    Takano M, Kuratomi S (2003) Regulation of cardiac inwardly rectifying potassium channels by membrane lipid metabolism. Progr Biophys Mol Biol 81:67–79.  https://doi.org/10.1016/S0079-6107(02)00048-2 CrossRefGoogle Scholar
  34. 34.
    ten Tusscher KHWJ, Noble D, Noble PJ, Panfilov AV (2004) A model for human ventricular tissue. Am J Physiol Heart Circ Physiol 286:H1573–H1589.  https://doi.org/10.1152/ajpheart.00794.2003 CrossRefPubMedGoogle Scholar
  35. 35.
    Wang Z, Yue L, White M, Pelletier G, Nattel S (1998) Differential distribution of inward rectifier potassium channel transcripts in human atrium versus ventricle. Circulation 98:2422–2428.  https://doi.org/10.1161/​01.CIR.98.22.2422 CrossRefPubMedGoogle Scholar
  36. 36.
    Xie LH, John SA, Ribalet B, Weiss JN (2005) Long polyamines act as cofactors in PIP2 activation of inward rectifier potassium (Kir2.1) channels. J Gen Physiol 126:541–549.  https://doi.org/10.1085/jgp.200509380 CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Xie LH, John SA, Ribalet B, Weiss JN (2007) Activation of inwardly rectifying potassium (Kir) channels by phosphatidylinosital-4,5-bisphosphate (PIP2): interaction with other regulatory ligands. Prog Biophys Mol Biol 94:320–335.  https://doi.org/10.1016/j.pbiomolbio.2006.04.001 CrossRefPubMedGoogle Scholar
  38. 38.
    Xie LH, John SA, Ribalet B, Weiss JN (2008) Phosphatidylinositol-4,5-bisphosphate (PIP2) regulation of strong inward rectifier Kir2.1 channels: multilevel positive cooperativity. J Physiol 586:1833–1848.  https://doi.org/10.1113/jphysiol.2007.147868 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Yan DH, Ishihara K (2005) Two Kir2.1 channel populations with different sensitivities to Mg2+ and polyamine block: a model for the cardiac strong inward rectifier K+ channel. J Physiol 563:725–744.  https://doi.org/10.1113/jphysiol.2004.079186 CrossRefPubMedGoogle Scholar
  40. 40.
    Zobel C, Cho HC, Nguyen TT, Pekhletski R, Diaz RJ, Wilson GJ, Backx PH (2003) Molecular dissection of the inward rectifier potassium current (I K1) in rabbit cardiomyocytes: evidence for heteromeric coassembly of Kir2.1 and Kir2.2. J Physiol 550:365–372.  https://doi.org/10.1113/jphysiol.2002.036400 CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Zuo Y, Aistrup GL, Marszalec W, Gillespie A, Chavez-Noriega LE, Yeh JZ, Narahashi T (2001) Dual action of n-alcohols on neuronal nicotinic acetylcholine receptors. Mol Pharmacol 6:700–711Google Scholar

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  1. 1.Department of Physiology, Faculty of MedicineMasaryk UniversityBrnoCzech Republic

Personalised recommendations