Advertisement

Kir2.1 channels set two levels of resting membrane potential with inward rectification

  • Kuihao Chen
  • Dongchuan Zuo
  • Zheng Liu
  • Haijun ChenEmail author
Ion channels, receptors and transporters
Part of the following topical collections:
  1. Ion channels, receptors and transporters

Abstract

Strong inward rectifier K+ channels (Kir2.1) mediate background K+ currents primarily responsible for maintenance of resting membrane potential. Multiple types of cells exhibit two levels of resting membrane potential. Kir2.1 and K2P1 currents counterbalance, partially accounting for the phenomenon of human cardiomyocytes in subphysiological extracellular K+ concentrations or pathological hypokalemic conditions. The mechanism of how Kir2.1 channels contribute to the two levels of resting membrane potential in different types of cells is not well understood. Here we test the hypothesis that Kir2.1 channels set two levels of resting membrane potential with inward rectification. Under hypokalemic conditions, Kir2.1 currents counterbalance HCN2 or HCN4 cation currents in CHO cells that heterologously express both channels, generating N-shaped current-voltage relationships that cross the voltage axis three times and reconstituting two levels of resting membrane potential. Blockade of HCN channels eliminated the phenomenon in K2P1-deficient Kir2.1-expressing human cardiomyocytes derived from induced pluripotent stem cells or CHO cells expressing both Kir2.1 and HCN2 channels. Weakly inward rectifier Kir4.1 or inward rectification-deficient Kir2.1•E224G mutant channels do not set such two levels of resting membrane potential when co-expressed with HCN2 channels in CHO cells or when overexpressed in human cardiomyocytes derived from induced pluripotent stem cells. These findings demonstrate a common mechanism that Kir2.1 channels set two levels of resting membrane potential with inward rectification by balancing inward currents through different cation channels such as hyperpolarization-activated HCN channels or hypokalemia-induced K2P1 leak channels.

Keywords

Kir2.1 channel Inward rectification Resting membrane potential HCN channel Cardiomyocyte 

Abbreviations

HCN

Hyperpolarization-activated cyclic nucleotide-gated cation channel

iPSC

Induced pluripotent stem cells

I-V

Current-voltage

Kir2.1

Inward rectifier K+ channel subfamily 2 isoform 1

K2P1

Two pore-domain K+ channel isoform 1

Notes

Acknowledgements

We thank Steven A. Siegelbaum, Juliane Stieber, and Catherine Proenza for providing HCN plasmids and Stephen J. Tucker for providing rat Kir4.1 plasmids.

Author contributions

HC, DZ, KC, and ZL designed the research; HC, DZ, and KC analyzed data; DZ and KC performed the research; and HC, DZ, and KC wrote the paper.

Funding information

This work was supported by the National Institute of General Medical Sciences, NIH (R01GM102943) and the National Natural Science Foundation of China (81370296, 81370297, and 81570303).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

References

  1. 1.
    Anumonwo JM, Lopatin AN (2010) Cardiac strong inward rectifier potassium channels. J Mol Cell Cardiol 48(1):45–54.  https://doi.org/10.1016/j.yjmcc.2009.08.013 CrossRefPubMedGoogle Scholar
  2. 2.
    Biel M, Wahl-Schott C, Michalakis S, Zong X (2009) Hyperpolarization-activated cation channels: from genes to function. Physiol Rev 89(3):847–885.  https://doi.org/10.1152/physrev.00029.2008 CrossRefPubMedGoogle Scholar
  3. 3.
    Cannon SC (2015) Channelopathies of skeletal muscle excitability. Compr Physiol 5(2):761–790.  https://doi.org/10.1002/cphy.c140062 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Christe G (1982) Effects of low [K+]o on the electrical activity of human cardiac ventricular and Purkinje cells. Cardiovasc Res 17:243–250CrossRefGoogle Scholar
  5. 5.
    Cui J (2016) Voltage-dependent gating: novel insights from KCNQ1 channels. Biophys J 110(1):14–25.  https://doi.org/10.1016/j.bpj.2015.11.023 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Doss MX, Di Diego JM, Goodrow RJ, Wu Y, Cordeiro JM, Nesterenko VV, Barajas-Martinez H, Hu D, Urrutia J, Desai M, Treat JA, Sachinidis A, Antzelevitch C (2012) Maximum diastolic potential of human induced pluripotent stem cell-derived cardiomyocytes depends critically on I(Kr). PLoS One 7:e40288.  https://doi.org/10.1371/journal.pone.0040288 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Ellis D (1977) The effects of external cations and ouabain on the intracellular sodium activity of sheep heart Purkinje fibres. J Physiol 273(1):211–240.  https://doi.org/10.1113/jphysiol.1977.sp012090 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Gadsby DC, Cranefield PF (1977) Two levels of resting potential in cardiac Purkinje fibers. J Gen Physiol 70(6):725–746.  https://doi.org/10.1085/jgp.70.6.725 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Gallaher J, Bier M, van Heukelom JS (2010) First order phase transition and hysteresis in a cell’s maintenance of the membrane potential—an essential role for the inward potassium rectifiers. Bio Systems 101(3):149–155.  https://doi.org/10.1016/j.biosystems.2010.05.007 CrossRefPubMedGoogle Scholar
  10. 10.
    Gallin EK (1981) Voltage clamp studies in macrophages from mouse spleen cultures. Science 214(4519):458–460.  https://doi.org/10.1126/science.7291986 CrossRefPubMedGoogle Scholar
  11. 11.
    Gallin EK, Livengood DR (1981) Inward rectification in mouse macrophages: evidence for a negative resistance region. Am J Phys 241:C9–17CrossRefGoogle Scholar
  12. 12.
    Geukes Foppen RJ, van Mil HG, van Heukelom JS (2002) Effects of chloride transport on bistable behaviour of the membrane potential in mouse skeletal muscle. J Physiol 542(1):181–191.  https://doi.org/10.1113/jphysiol.2001.013298 CrossRefPubMedGoogle Scholar
  13. 13.
    Herrmann S, Hofmann F, Stieber J, Ludwig A (2012) HCN Channels in the heart: lessons from mouse mutants. Br J Pharmacol 166(2):501–509.  https://doi.org/10.1111/j.1476-5381.2011.01798.x CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    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(1):291–366.  https://doi.org/10.1152/physrev.00021.2009 CrossRefPubMedGoogle Scholar
  15. 15.
    Hoekstra M, Mummery CL, Wilde AA, Bezzina CR, Verkerk AO (2012) Induced pluripotent stem cell derived cardiomyocytes as models for cardiac arrhythmias. Front Physiol 3:346CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Jurkat-Rott K, Weber MA, Fauler M, Guo XH, Holzherr BD, Paczulla A, Nordsborg N, Joechle W, Lehmann-Horn F (2009) K+-dependent paradoxical membrane depolarization and Na+ overload, major and reversible contributors to weakness by ion channel leaks. Proc Natl Acad Sci U S A 106(10):4036–4041.  https://doi.org/10.1073/pnas.0811277106 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Kubo Y, Murata Y (2001) Control of rectification and permeation by two distinct sites after the second transmembrane region in Kir2.1 K+ channel. J Physiol 531(3):645–660.  https://doi.org/10.1111/j.1469-7793.2001.0645h.x CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Lee CO, Fozzard HA (1979) Membrane permeability during low potassium depolarization in sheep cardiac Purkinje fibers. Am J Phys 237:C156–C165CrossRefGoogle Scholar
  19. 19.
    Lieu DK, Fu JD, Chiamvimonvat N, Tung KC, McNerney GP, Huser T, Keller G, Kong CW, Li RA (2013) Mechanism-based facilitated maturation of human pluripotent stem cell-derived cardiomyocytes. Circ Arrhythm Electrophysiol 6(1):191–201.  https://doi.org/10.1161/CIRCEP.111.973420 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Lopatin AN, Nichols CG (2001) Inward rectifiers in the heart: an update on I(K1). J Mol Cell Cardiol 33(4):625–638.  https://doi.org/10.1006/jmcc.2001.1344 CrossRefPubMedGoogle Scholar
  21. 21.
    Ma J, Guo L, Fiene SJ, Anson BD, Thomson JA, Kamp TJ, Kolaja KL, Swanson BJ, January CT (2011) High purity human-induced pluripotent stem cell-derived cardiomyocytes: electrophysiological properties of action potentials and ionic currents. Am J Physiol Heart Circ Physiol 301(5):H2006–H2017.  https://doi.org/10.1152/ajpheart.00694.2011 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Ma L, Zhang X, Chen H (2011) TWIK-1 two-pore domain potassium channels change ion selectivity and conduct inward leak sodium currents in hypokalemia. Sci Signal 4:ra37CrossRefPubMedGoogle Scholar
  23. 23.
    McCullough JR, Chua WT, Rasmussen HH, Ten Eick RE, Singer DH (1990) Two stable levels of diastolic potential at physiological K+ concentrations in human ventricular myocardial cells. Circ Res 66(1):191–201.  https://doi.org/10.1161/01.RES.66.1.191 CrossRefPubMedGoogle Scholar
  24. 24.
    Miura DS, Hoffman BF, Rosen MR (1977) The effect of extracellular potassium on the intracellular potassium ion activity and transmembrane potentials of beating canine cardiac Purkinje fibers. J Gen Physiol 69(4):463–474.  https://doi.org/10.1085/jgp.69.4.463 CrossRefPubMedGoogle Scholar
  25. 25.
    Proenza C, Yellen G (2006) Distinct populations of HCN pacemaker channels produce voltage-dependent and voltage-independent currents. J Gen Physiol 127(2):183–190.  https://doi.org/10.1085/jgp.200509389 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Rastegar A, Soleimani M (2001) Hypokalaemia and hyperkalaemia. Postgrad Med J 77(914):759–764.  https://doi.org/10.1136/pmj.77.914.759 CrossRefPubMedGoogle Scholar
  27. 27.
    Ravesloot JH, Ypey DL, Vrijheid-Lammers T, Nijweide PJ (1989) Voltage-activated K+ conductances in freshly isolated embryonic chicken osteoclasts. Proc Natl Acad Sci U S A 86(17):6821–6825.  https://doi.org/10.1073/pnas.86.17.6821 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Roubille F, Tardif JC (2013) New therapeutic targets in cardiology: heart failure and arrhythmia: HCN channels. Circulation 127(19):1986–1996.  https://doi.org/10.1161/CIRCULATIONAHA.112.000145 CrossRefPubMedGoogle Scholar
  29. 29.
    Shah AK, Cohen IS, Datyner NB (1987) Background K+ current in isolated canine cardiac Purkinje myocytes. Biophys J 52(4):519–525.  https://doi.org/10.1016/S0006-3495(87)83241-1 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Sheu SS, Korth M, Lathrop DA, Fozzard HA (1980) Intra- and extracellular K+ and Na+ activities and resting membrane potential in sheep cardiac purkinje strands. Circ Res 47(5):692–700.  https://doi.org/10.1161/01.RES.47.5.692 CrossRefPubMedGoogle Scholar
  31. 31.
    Siegenbeek van Heukelom J (1991) Role of the anomalous rectifier in determining membrane potentials of mouse muscle fibres at low extracellular K+. J Physiol 434(1):549–560.  https://doi.org/10.1113/jphysiol.1991.sp018485 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Sims SM, Dixon SJ (1989) Inwardly rectifying K+ current in osteoclasts. Am J Phys 256:C1277–C1282CrossRefGoogle Scholar
  33. 33.
    Struyk AF, Cannon SC (2008) Paradoxical depolarization of BA2+-treated muscle exposed to low extracellular K+: insights into resting potential abnormalities in hypokalemic paralysis. Muscle Nerve 37(3):326–337.  https://doi.org/10.1002/mus.20928 CrossRefPubMedGoogle Scholar
  34. 34.
    Ten Eick RE, Singer DH (1979) Electrophysiological properties of diseased human atrium. I. Low diastolic potential and altered cellular response to potassium. Circ Res 44(4):545–557.  https://doi.org/10.1161/01.RES.44.4.545 CrossRefPubMedGoogle Scholar
  35. 35.
    Wiggins JR, Cranefield PF (1976) Two levels of resting potential in canine cardiac Purkinje fibers exposed to sodium-free solutions. Circ Res 39(4):466–474.  https://doi.org/10.1161/01.RES.39.4.466 CrossRefPubMedGoogle Scholar
  36. 36.
    Yang J, Jan YN, Jan LY (1995) Control of rectification and permeation by residues in two distinct domains in an inward rectifier K+ channel. Neuron 14(5):1047–1054.  https://doi.org/10.1016/0896-6273(95)90343-7 CrossRefPubMedGoogle Scholar
  37. 37.
    Zaza A (2009) Serum potassium and arrhythmias. Europace 11(4):421–422.  https://doi.org/10.1093/europace/eup005 CrossRefPubMedGoogle Scholar
  38. 38.
    Zhou M, Xu G, Xie M, Zhang X, Schools GP, Ma L, Kimelberg HK, Chen H (2009) TWIK-1 and TREK-1 are potassium channels contributing significantly to astrocyte passive conductance in rat hippocampal slices. J Neurosci 29(26):8551–8564.  https://doi.org/10.1523/JNEUROSCI.5784-08.2009 CrossRefPubMedGoogle Scholar
  39. 39.
    Zuo D, Chen K, Zhou M, Liu Z, Chen H (2017) Kir2.1 and K2P1 channels reconstitute two levels of resting membrane potential in cardiomyocytes. J Physiol 595(15):5129–5142.  https://doi.org/10.1113/JP274268 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  1. 1.Department of Biological SciencesUniversity at Albany, State University of New YorkAlbanyUSA
  2. 2.Department of Cardiology, Shanghai Tenth People’s HospitalTongji University School of MedicineShanghaiChina

Personalised recommendations