From Two Competing Oscillators to One Coupled-clock Pacemaker Cell System

Overview

Journal Front Physiol

Date 2015 Mar 6

PMID 25741284

Citations 64

Authors

Yael Yaniv

Edward G Lakatta

Victor A Maltsev

Affiliations

Soon will be listed here.

Abstract

At the beginning of this century, debates regarding "what are the main control mechanisms that ignite the action potential (AP) in heart pacemaker cells" dominated the electrophysiology field. The original theory which prevailed for over 50 years had advocated that the ensemble of surface membrane ion channels (i.e., "M-clock") is sufficient to ignite rhythmic APs. However, more recent experimental evidence in a variety of mammals has shown that the sarcoplasmic reticulum (SR) acts as a "Ca(2+)-clock" rhythmically discharges diastolic local Ca(2+) releases (LCRs) beneath the cell surface membrane. LCRs activate an inward current (likely that of the Na(+)/Ca(2+) exchanger) that prompts the surface membrane "M-clock" to ignite an AP. Theoretical and experimental evidence has mounted to indicate that this clock "crosstalk" operates on a beat-to-beat basis and determines both the AP firing rate and rhythm. Our review is focused on the evolution of experimental definition and numerical modeling of the coupled-clock concept, on how mechanisms intrinsic to pacemaker cell determine both the heart rate and rhythm, and on future directions to develop further the coupled-clock pacemaker cell concept.

Citing Articles

The mechano-electric feedback mediates the dual effect of stretch in mouse sinoatrial tissue.

Arbel Ganon L, Eid R, Hamra M, Yaniv Y J Mol Cell Cardiol Plus. 2025; 5():100042.

PMID: 39802174 PMC: 11708250. DOI: 10.1016/j.jmccpl.2023.100042.

Modelling pacemaker oscillations in lymphatic muscle cells: lengthened action potentials by two distinct system effects.

Hancock E, Macaskill C, Zawieja S, Davis M, Bertram C R Soc Open Sci. 2025; 12(1):241714.

PMID: 39780965 PMC: 11706657. DOI: 10.1098/rsos.241714.

Cardiac conduction diseases: understanding the molecular mechanisms to uncover targets for future treatments.

Li T, Marashly Q, Kim J, Li N, Chelu M Expert Opin Ther Targets. 2024; 28(5):385-400.

PMID: 38700451 PMC: 11395937. DOI: 10.1080/14728222.2024.2351501.

A dual-clock-driven model of lymphatic muscle cell pacemaking to emulate knock-out of Ano1 or IP3R.

Hancock E, Zawieja S, Macaskill C, Davis M, Bertram C J Gen Physiol. 2023; 155(12).

PMID: 37851028 PMC: 10585120. DOI: 10.1085/jgp.202313355.

IP3R1 underlies diastolic ANO1 activation and pressure-dependent chronotropy in lymphatic collecting vessels.

Zawieja S, Pea G, Broyhill S, Patro A, Bromert K, Li M J Gen Physiol. 2023; 155(12).

PMID: 37851027 PMC: 10585095. DOI: 10.1085/jgp.202313358.

References

Maltsev V, Lakatta E . Numerical models based on a minimal set of sarcolemmal electrogenic proteins and an intracellular Ca(2+) clock generate robust, flexible, and energy-efficient cardiac pacemaking. J Mol Cell Cardiol. 2013; 59:181-95. PMC: 4538696. DOI: 10.1016/j.yjmcc.2013.03.004. View

Christel C, Cardona N, Mesirca P, Herrmann S, Hofmann F, Striessnig J . Distinct localization and modulation of Cav1.2 and Cav1.3 L-type Ca2+ channels in mouse sinoatrial node. J Physiol. 2012; 590(24):6327-42. PMC: 3533195. DOI: 10.1113/jphysiol.2012.239954. View

Mesirca P, Torrente A, Mangoni M . T-type channels in the sino-atrial and atrioventricular pacemaker mechanism. Pflugers Arch. 2014; 466(4):791-9. DOI: 10.1007/s00424-014-1482-6. View

Ju Y, Woodcock E, Allen D, Cannell M . Inositol 1,4,5-trisphosphate receptors and pacemaker rhythms. J Mol Cell Cardiol. 2012; 53(3):375-81. DOI: 10.1016/j.yjmcc.2012.06.004. View

Yang J, Huang J, Maity B, Gao Z, Lorca R, Gudmundsson H . RGS6, a modulator of parasympathetic activation in heart. Circ Res. 2010; 107(11):1345-9. PMC: 2997524. DOI: 10.1161/CIRCRESAHA.110.224220. View

Yaniv Y, Lyashkov A, Sirenko S, Okamoto Y, Guiriba T, Ziman B . Stochasticity intrinsic to coupled-clock mechanisms underlies beat-to-beat variability of spontaneous action potential firing in sinoatrial node pacemaker cells. J Mol Cell Cardiol. 2014; 77:1-10. PMC: 4312254. DOI: 10.1016/j.yjmcc.2014.09.008. View

Scouarnec S, Bhasin N, Vieyres C, Hund T, Cunha S, Koval O . Dysfunction in ankyrin-B-dependent ion channel and transporter targeting causes human sinus node disease. Proc Natl Acad Sci U S A. 2008; 105(40):15617-22. PMC: 2563133. DOI: 10.1073/pnas.0805500105. View

Himeno Y, Toyoda F, Satoh H, Amano A, Cha C, Matsuura H . Minor contribution of cytosolic Ca2+ transients to the pacemaker rhythm in guinea pig sinoatrial node cells. Am J Physiol Heart Circ Physiol. 2010; 300(1):H251-61. DOI: 10.1152/ajpheart.00764.2010. View

Butters T, Aslanidi O, Inada S, Boyett M, Hancox J, Lei M . Mechanistic links between Na+ channel (SCN5A) mutations and impaired cardiac pacemaking in sick sinus syndrome. Circ Res. 2010; 107(1):126-37. PMC: 2901593. DOI: 10.1161/CIRCRESAHA.110.219949. View

10.

Maltsev V, Yaniv Y, Maltsev A, Stern M, Lakatta E . Modern perspectives on numerical modeling of cardiac pacemaker cell. J Pharmacol Sci. 2014; 125(1):6-38. PMC: 4530975. DOI: 10.1254/jphs.13r04cr. View

11.

Monfredi O, Maltseva L, Spurgeon H, Boyett M, Lakatta E, Maltsev V . Beat-to-Beat Variation in Periodicity of Local Calcium Releases Contributes to Intrinsic Variations of Spontaneous Cycle Length in Isolated Single Sinoatrial Node Cells. PLoS One. 2013; 8(6):e67247. PMC: 3695077. DOI: 10.1371/journal.pone.0067247. View

12.

Herrmann S, Stieber J, Stockl G, Hofmann F, Ludwig A . HCN4 provides a 'depolarization reserve' and is not required for heart rate acceleration in mice. EMBO J. 2007; 26(21):4423-32. PMC: 2063478. DOI: 10.1038/sj.emboj.7601868. View

13.

Voigt N, Heijman J, Wang Q, Chiang D, Li N, Karck M . Cellular and molecular mechanisms of atrial arrhythmogenesis in patients with paroxysmal atrial fibrillation. Circulation. 2013; 129(2):145-156. PMC: 4342412. DOI: 10.1161/CIRCULATIONAHA.113.006641. View

14.

Qu Z, Garfinkel A, Weiss J, Nivala M . Multi-scale modeling in biology: how to bridge the gaps between scales?. Prog Biophys Mol Biol. 2011; 107(1):21-31. PMC: 3190585. DOI: 10.1016/j.pbiomolbio.2011.06.004. View

15.

Yaniv Y, Maltsev V, Escobar A, Spurgeon H, Ziman B, Stern M . Beat-to-beat Ca(2+)-dependent regulation of sinoatrial nodal pacemaker cell rate and rhythm. J Mol Cell Cardiol. 2011; 51(6):902-5. PMC: 3208800. DOI: 10.1016/j.yjmcc.2011.08.029. View

16.

Hof T, Simard C, Rouet R, Salle L, Guinamard R . Implication of the TRPM4 nonselective cation channel in mammalian sinus rhythm. Heart Rhythm. 2013; 10(11):1683-9. DOI: 10.1016/j.hrthm.2013.08.014. View

17.

Ju Y, Liu J, Lee B, Lai D, Woodcock E, Lei M . Distribution and functional role of inositol 1,4,5-trisphosphate receptors in mouse sinoatrial node. Circ Res. 2011; 109(8):848-57. DOI: 10.1161/CIRCRESAHA.111.243824. View

18.

Verheijck E, Wilders R, Joyner R, Golod D, Kumar R, Jongsma H . Pacemaker synchronization of electrically coupled rabbit sinoatrial node cells. J Gen Physiol. 1998; 111(1):95-112. PMC: 1887765. DOI: 10.1085/jgp.111.1.95. View

19.

Maltsev V, Vinogradova T, Stern M, Lakatta E . Letter to the editor: "Validating the requirement for beat-to-beat coupling of the Ca2+ clock and M clock in pacemaker cell normal automaticity". Am J Physiol Heart Circ Physiol. 2011; 300(6):H2323-4. PMC: 3119099. DOI: 10.1152/ajpheart.00110.2011. View

20.

Demion M, Bois P, Launay P, Guinamard R . TRPM4, a Ca2+-activated nonselective cation channel in mouse sino-atrial node cells. Cardiovasc Res. 2006; 73(3):531-8. DOI: 10.1016/j.cardiores.2006.11.023. View