Abstract
Atrial fibrillation (AF), a cardiac arrhythmia characterized by an abnormal heart rythm originated in the atria, is one of the most prevalent cardiac diseases. Although it may have diverse causes, genetic screening has shown that a percentage of pacients suffering of AF present a genetic variant related to disregulation of calcium-activated potassium (SK) channels. In this paper we review the main characteristics of these channels and use several mathematical models of human atrial cardiomyocytes to study their influence in the form of the atrial action potential. We show that an overexpression of SK channels results in decreased action potential duration and, under some circumstances, it may give rise to alternans, suggesting a pro-arrhythmic role of this current. This effect becomes more important at higher pacing rates. Nevertheless, we also find it to protect against spontaneous calcium release induced afterdepolarizations, acting in this case as an antiarrhythmic factor.
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References
Adelman, J.P., Maylie, J., Sah, P.: Small-conductance Ca2+-activated K+ channels: form and function. Annu. Rev. Physiol. 74, 245–269 (2012)
Berkefeld, H., Fakler, B., Schulte, U.: Ca2+-activated K+ channels: from protein complexes to function. Physiol. Rev. 90(4), 1437–1459 (2010)
Blatz, A.L., Magleby, K.L.: Single apamin-blocked ca-activated K+ channels of small conductance in cultured rat skeletal muscle. Nature 323(1), 718–720 (1986)
Carignani, C., Roncarati, R., Rimini, R., Terstappen, G.C.: Pharmacological and molecular characterisation of SK3 channels in the TE671 human medulloblastoma cell line. Brain Res. 939, 11–18 (2002)
Cha, C.Y., Nakamura, Y., Himeno, Y., Wang, J., Fujimoto, S., Inagaki, N., Earm, Y.E., Noma, A.: Ionic mechanisms and Ca2+ dynamics underlying the glucose response of pancreatic \(\beta \) cells: a simulation study. J. Gen. Physiol. 138(1), 21–37 (2011)
Chay, T.R.: Effects of extracellular calcium on electrical bursting and intracellular and luminal calcium oscillations in insulin secreting pancreatic beta-cells. Biophys. J. 73(3), 1673 (1997)
Chen, W.-T., Chen, Y.-C., Lu, Y.-Y., Kao, Y.-H., Huang, J.-H., Lin, Y.-K., Chen, S.-A., Chen, Y.-J.: Apamin modulates electrophysiological characteristics of the pulmonary vein and the sinoatrial node. Eur. J. Clin. Investig. 43(9), 957–963 (2013)
Chua, S.-K., Chang, P.-C., Maruyama, M., Turker, I., Shinohara, T., Shen, M.J., Chen, Z., Shen, C., Rubart-von der Lohe, M., Lopshire, J.C., et al.: Small-conductance calcium-activated potassium channel and recurrent ventricular fibrillation in failing rabbit ventricles. Circ. Res. 108(8), 971–979 (2011)
Commons, W.: File:sk channel.jpg—wikimedia commons, the free media repository (2018). Accessed 21 Jan 2019
Courtemanche, M., Ramirez, R.J., Nattel, S.: Ionic mechanisms underlying human atrial action potential properties: insights from a mathematical model. Am. J. Physiol.-Hear. Circ. Physiol. 275(1), H301–H321 (1998)
Destexhe, A., Contreras, D., Sejnowski, T.J., Steriade, M.: A model of spindle rhythmicity in the isolated thalamic reticular nucleus. J. Neurophysiol. 72(2), 803–818 (1994)
Diness, J.G., Skibsbye, L., Jespersen, T., Bartels, E.D., Sørensen, U.S., Hansen, R.S., Grunnet, M.: Effects on atrial fibrillation in aged hypertensive rats by Ca2+-activated K+ channel inhibition. Hypertension 57(6), 1129–1135 (2011)
Diness, J.G., Sørensen, U.S., Nissen, J.D., Al-Shahib, B., Jespersen, T., Grunnet, M., Hansen, R.S.: Inhibition of small-conductance Ca2+-activated K+ channels terminates and protects against atrial fibrillation. Circulation: Arrhythmia Electrophysiol. 3(4), 380–390 (2010)
Ellinor, P.T., Lunetta, K.L., Glazer, N.L., Pfeufer, A., Alonso, A., Chung, M.K., Sinner, M.F., De Bakker, P.I., Mueller, M., Lubitz, S.A., et al.: Common variants in KCNN3 are associated with lone atrial fibrillation. Nat. Genet. 42(3), 240–244 (2010)
Engel, J., Schultens, H.A., Schild, D.: Small conductance potassium channels cause an activity-dependent spike frequency adaptation and make the transfer function of neurons logarithmic. Biophys. J. 76(3), 1310–1319 (1999)
Fridlyand, L.E., Jacobson, D., Kuznetsov, A., Philipson, L.H.: A model of action potentials and fast Ca2+ dynamics in pancreatic \(\beta \)-cells. Biophys. J. 96(8), 3126–3139 (2009)
Goforth, P., Bertram, R., Khan, F., Zhang, M., Sherman, A., Satin, L.: Calcium-activated k+ channels of mouse \(\beta \)-cells are controlled by both store and cytoplasmic ca2+ experimental and theoretical studies. J. Gen. Physiol. 120(3), 307–322 (2002)
Grandi, E., Pandit, S.V., Voigt, N., Workman, A.J., Dobrev, D., Jalife, J., Bers, D.M.: Human atrial action potential and Ca2+ model. Circ. Res. 109, 1055–1066 (2011). https://doi.org/10.1161/CIRCRESAHA.111.253955
Hille, B., et al.: Lon Channels Of Excitable Membranes, vol. 507. Sinauer Sunderland, MA (2001)
Hirschberg, B., Maylie, J., Adelman, J.P., Marrion, N.V.: Gating of recombinant small-conductance ca-activated K+ channels by calcium. J. Gen. Physiol. 111(4), 565–581 (1998)
Hsueh, C.-H., Chang, P.-C., Hsieh, Y.-C., Reher, T., Chen, P.-S., Lin, S.-F.: Proarrhythmic effect of blocking the small conductance calcium activated potassium channel in isolated canine left atrium. Heart Rhythm 10(6), 891–898 (2013)
Kennedy, M., Bers, D.M., Chiamvimonvat, N., Sato, D.: Dynamical effects of calcium-sensitive potassium currents on voltage and calcium alternans. J. Physiol. (2016)
Kohler, M., Hirschberg, B., Bond, C., Kinzie, J.M., et al.: Small-conductance, calcium-activated potassium channels from mammalian brain. Science 273(5282), 1709 (1996)
Leinders, T., Vijverberg, H.: Ca2+ dependence of small Ca2+-activated K+ channels in cultured N1E-115 mouse neuroblastoma cells. Pflügers Arch. 422(3), 223–232 (1992)
Li, N., Timofeyev, V., Tuteja, D., Xu, D., Lu, L., Zhang, Q., Zhang, Z., Singapuri, A., Albert, T.R., Rajagopal, A.V., et al.: Ablation of a Ca2+-activated K+ channel (SK2 channel) results in action potential prolongation in atrial myocytes and atrial fibrillation. J. Physiol. 587(5), 1087–1100 (2009)
Ling, T.-Y., Wang, X.-L., Chai, Q., Lau, T.-W., Koestler, C.M., Park, S.J., Daly, R.C., Greason, K.L., Jen, J., Wu, L.-Q., et al.: Regulation of the SK3 channel by microRNA-499—potential role in atrial fibrillation. Heart Rhythm 10(7), 1001–1009 (2013)
Lu, L., Zhang, Q., Timofeyev, V., Zhang, Z., Young, J.N., Shin, H.-S., Knowlton, A.A., Chiamvimonvat, N.: Molecular coupling of a Ca2+-activated K+ channel to l-type Ca2+ channels via \(\alpha \)-actinin2. Circ. Res. 100(1), 112–120 (2007)
Lugo, C.A., Cantalapiedra, I.R., Peñaranda, A., Hove-Madsen, L., Echebarria, B.: Are SR Ca content fluctuations or SR refractoriness the key to atrial cardiac alternans?: insights from a human atrial model. Am. J. Physiol.-Heart Circ. Physiol. 306(11), H1540–H1552 (2014). https://doi.org/10.1152/ajpheart.00515.2013
Mears, D., Sheppard Jr., N., Atwater, I., Rojas, E., Bertram, R., Sherman, A.: Evidence that calcium release-activated current mediates the biphasic electrical activity of mouse pancreatic \(\beta \)-cells. J. Membr. Biol. 155(1), 47–59 (1997)
Mu, Y.-H., Zhao, W.-C., Duan, P., Chen, Y., Wang, Q., Tu, H.-Y., Zhang, Q., et al.: RyR2 modulates a Ca2+-activated K+ current in mouse cardiac myocytes. PloS one 9(4), e94905 (2014)
Nattel, S., Qi, X.Y.: Calcium-dependent potassium channels in the heart: clarity and confusion. Cardiovasc. Res. 101(2), 185–186 (2014). https://doi.org/10.1093/cvr/cvt340
Nygren, A., Fiset, C., Firek, L., Clark, J., Lindblad, D., Clark, R., Giles, W.: Mathematical model of an adult human atrial cell. Cardiovasc. Res. 82(1), 63–81 (1998)
Olesen, M.S., Jabbari, J., Holst, A.G., Nielsen, J.B., Steinbrüchel, D.A., Jespersen, T., Haunsø, S., Svendsen, J.H.: Screening of KCNN3 in patients with early-onset lone atrial fibrillation. Europace 13(7), 963–967 (2011)
Özgen, N., Dun, W., Sosunov, E.A., Anyukhovsky, E.P., Hirose, M., Duffy, H.S., Boyden, P.A., Rosen, M.R.: Early electrical remodeling in rabbit pulmonary vein results from trafficking of intracellular SK2 channels to membrane sites. Cardiovasc. Res. 75(4), 758–769 (2007)
Qi, X.-Y., Diness, J.G., Brundel, B.J., Zhou, X.-B., Naud, P., Wu, C.-T., Huang, H., Harada, M., Aflaki, M., Dobrev, D., et al.: Role of small-conductance calcium-activated potassium channels in atrial electrophysiology and fibrillation in the dog. Circulation 129(4), 430–440 (2014)
Rafizadeh, S., Zhang, Z., Woltz, R.L., Kim, H.J., Myers, R.E., Lu, L., Tuteja, D., Singapuri, A., Bigdeli, A.A.Z., Harchache, S.B., et al.: Functional interaction with filamin a and intracellular Ca2+ enhance the surface membrane expression of a small-conductance Ca2+-activated K+ (SK2) channel. Proc. Natl. Acad. Sci. 111(27), 9989–9994 (2014)
Skibsbye, L.: Antiarrhythmic principle of SK channel inhibition in atrial fibrillation. Channels 57, 672–681 (2011)
Skibsbye, L., Diness, J.G., Sørensen, U.S., Hansen, R.S., Grunnet, M.: The duration of pacing-induced atrial fibrillation is reduced in vivo by inhibition of small conductance Ca2+-activated K+ channels. J. Cardiovasc. Pharmacol. 57(6), 672–681 (2011)
Skibsbye, L., Poulet, C., Diness, J.G., Bentzen, B.H., Yuan, L., Kappert, U., Matschke, K., Wettwer, E., Ravens, U., Grunnet, M., et al.: Small-conductance calcium-activated potassium (SK) channels contribute to action potential repolarization in human atria. Cardiovasc. Res. 103(1), 156–167 (2014)
Stocker, M.: Ca2+-activated K+ channels: molecular determinants and function of the SK family. Nat. Rev. Neurosci. 5(10), 758–770 (2004)
Terentyev, D., Rochira, J.A., Terentyeva, R., Roder, K., Koren, G., Li, W.: Sarcoplasmic reticulum Ca2+ release is both necessary and sufficient for SK channel activation in ventricular myocytes. Am. J. Physiol.-Heart Circ. Physiol. 306(5), H738–H746 (2014)
Tucker, T.R., Fettiplace, R.: Monitoring calcium in turtle hair cells with a calcium-activated potassium channel. J. Physiol. 494(Pt 3), 613 (1996)
Tuteja, D., Xu, D., Timofeyev, V., Lu, L., Sharma, D., Zhang, Z., Xu, Y., Nie, L., Vázquez, A.E., Young, J.N., et al.: Differential expression of small-conductance Ca2+-activated K+ channels SK1, SK2, and SK3 in mouse atrial and ventricular myocytes. Am. J. Physiol.-Heart Circ. Physiol. 289(6), H2714–H2723 (2005)
Vergara, C., Latorre, R., Marrion, N.V., Adelman, J.P.: Calcium-activated potassium channels. Curr. Opin. Neurobiol. 8(3), 321–329 (1998)
Wang, W., Watanabe, M., Nakamura, T., Kudo, Y., Ochi, R.: Properties and expression of Ca2+-activated K+ channels in H9c2 cells derived from rat ventricle. Am. J. Physiol.-Heart Circ. Physiol. 276(5), H1559–H1566 (1999)
Xia, X.-M., Fakler, B., Rivard, A., Wayman, G., Johnson-Pais, T., Keen, J., Ishii, T., Hirschberg, B., Bond, C., Lutsenko, S., et al.: Mechanism of calcium gating in small-conductance calcium-activated potassium channels. Nature 395(6701), 503–507 (1998)
Xu, Y., Tuteja, D., Zhang, Z., Xu, D., Zhang, Y., Rodriguez, J., Nie, L., Tuxson, H.R., Young, J.N., Glatter, K.A., et al.: Molecular identification and functional roles of a Ca2+-activated K+ channel in human and mouse hearts. J. Biol. Chem. 278(49), 49085–49094 (2003)
Yu, T., Deng, C., Wu, R., Guo, H., Zheng, S., Yu, X., Shan, Z., Kuang, S., Lin, Q.: Decreased expression of small-conductance Ca2+-activated K+ channels SK1 and SK2 in human chronic atrial fibrillation. Life Sci. 90(5), 219–227 (2012)
Zhang, L., McBain, C.J.: Potassium conductances underlying repolarization and after-hyperpolarization in rat CA1 hippocampal interneurones. J. Physiol. 488(Pt 3), 661 (1995)
Zhang, X.-D., Lieu, D.K., Chiamvimonvat, N.: Small-conductance Ca2+-activated K+ channels and cardiac arrhythmias. Heart Rhythm 12(8), 1845–1851 (2015)
Zhang, X.-D., Timofeyev, V., Li, N., Myers, R.E., Zhang, D., Singapuri, A., Lau, V.C., Bond, C.T., Adelman, J., Lieu, D.K., et al.: Critical roles of a small conductance Ca2+-activated K+ channel (SK3) in the repolarization process of atrial myocytes. Cardiovasc. Res. 101(2), 317–325 (2013). https://doi.org/10.1093/cvr/cvt262
Acknowledgements
We thank L. Hove-Madsen for fruitful discussions. The authors acknowledge financial support from Fundació La Marató de TV3 and from the Spanish Ministerio de Economía y Competitividad (MINECO) under grant numbers SAF2014-58286-C2-2-R, SAF2017-88019-C3-2-R and FIS2015-66503-C3-2P. IRC also acknowledges financial support from the Generalitat of Catalonia under Project 2009SGR878.
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Peñaranda, A., Cantalapiedra, I.R., Alvarez-Lacalle, E., Echebarria, B. (2019). Electrophysiological Effects of Small Conductance Ca\(^{2+}\)-Activated K\(^+\) Channels in Atrial Myocytes. In: Carballido-Landeira, J., Escribano, B. (eds) Biological Systems: Nonlinear Dynamics Approach. SEMA SIMAI Springer Series, vol 20. Springer, Cham. https://doi.org/10.1007/978-3-030-16585-7_2
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