Christopher L.-H. Huang
R. John Solaro
Yunbo Ke
Ming Lei- 1Physiological Laboratory, Department of Biochemistry, University of Cambridge, Cambridge, UK
- 2Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, USA
- 3Department of Pharmacology, University of Oxford, Oxford, UK
The Editorial on the Research Topic
Ca2+ Signaling and Heart Rhythm
Ca2+ is a strategic intracellular second messenger regulating multifarious cardiac cellular processes. This Frontiers issue on Ca2+ signaling and cardiac rhythm first focuses on the spontaneous membrane depolarization triggering action potential (AP) pacing by sino-atrial node (SAN) cells. These drive normal rhythmic atrial followed by ventricular depolarization initiating effective systolic contraction (Mangoni and Nargeot, 2008). Classic pharmacological and immunological localization studies had implicated sarcoplasmic reticular (SR)-mediated Ca2+ storage and release (Rigg and Terrar, 1996) involving ryanodine receptor (RyR2)-Ca2+ release channels (Rigg et al., 2000) as necessary components in an adrenergically-responsive, complex, Ca2+-dependent, sino-atrial pacing process. Subsequent confocal imaging demonstrated spontaneous, precisely timed, rhythmic, local, submembrane, SR Ca2+ release events (Bogdanov et al., 2001; Vinogradova et al., 2004; Lakatta et al., 2010). Were these to activate Na+-Ca2+ exchange current, INCX, the resulting depolarization could trigger surface inward L-type Ca2+ currents, ICa, thereby initiating AP firing (Vinogradova et al., 2002). SAN cells possessed high basal cAMP and phosphokinase A-dependent phosphorylation levels (Vinogradova et al., 2006) that could ensure RyR2-mediated Ca2+ release activity (Yang et al., 2002) at the requisite frequencies (Vinogradova et al., 2002, 2006). The resulting [Ca2+] (to >100 nM) increases produced the expected INCX changes (Bogdanov et al., 2001) besides additionally activating strategic enzymes, particularly calcium/calmodulin-dependent protein kinase II (CaMKII). Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels carrying If likely also importantly contribute to this process: Hcn4-/- and Hcn4-R669Q/R669Q mouse embryos were bradycardic with 75–90% reduced If before eventual lethality (Stieber et al., 2003; Chandra et al., 2006; Harzheim et al., 2008); tamoxiphen-inducible adult hearts showed ~70% reduced If and progressive ≤50% reductions in, nevertheless persistent, SAN pacing, compromising its responses to isoproterenol challenge (Sohal et al., 2001; Baruscotti et al., 2011).
The present articles first complete necessary conditions for such a Ca2+-mediated pacing system (Vinogradova et al., 2000; Bogdanov et al., 2001; Sanders et al., 2006; Maltsev and Lakatta, 2007) to exist. They explore recent evidence implicating INCX, combined with delayed rectifier K+ current deactivation, in the pacemaker depolarization triggering ICa (Capel and Terrar). Furthermore, intracellular [Ca2+] proved instrumental in determining pacing rates: 1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid (BAPTA) dose-dependently slowed, ultimately abolishing, AP firing in isolated guinea-pig SAN myocytes (Capel and Terrar). Involvement of ICa in both SAN pacing and atrioventricular conduction was indicated in mice homozygously lacking L-type, Cav1.3, or T-type, Cav3.1, channels normally expressed in mouse, rabbit and human pacemaker tissue (Mesirca et al.). Volume and pressure overload-induced heart failure in rabbit SAN cells markedly influenced both Ca2+ transients and pacemaker activity (Verkerk et al.). Finally, the hypothesis generated schemes amenable to quantitative modeling and reconstruction (Yaniv et al.).
The articles then explore further ion channel mechanisms possibly contributing to this regulation. TRPC3 channels mediating Ca2+ entry are up-regulated in clinical and experimental atrial fibrillation (AF), and are implicated in SAN dysfunction and atrioventricular block (Yanni et al., 2011; Harada et al., 2012; Sabourin et al., 2012). Ju et al. report that the Trpc3-/- variant rescued pacing-induced AF in angiotensin II-treated mice (Ju et al.). Similarly, intracellular Ca2+ store depletion increased Ca2+ entry in isolated firing mouse SAN pacemaker cells, findings reduced by store-operated Ca2+ entry (SOCE) blockers. SAN pacemaker cells further expressed the endoplasmic reticular, Ca2+-sensing, stromal interacting molecules (STIM) and surface membrane Orai1 channels likely involved in SOCE. Ca2+ store depletion redistributed STIM1 to the cell periphery increasing STIM1-Ora1 co-localization (Liu et al.).
SAN and surrounding atrial tissue form a SAN-atrial pacemaker complex. SAN disorders accordingly can produce re-entrant substrate causing AF in addition to bradycardic, sinus node, dysfunction (Nattel et al., 2007). Altered intracellular Ca2+ transients and diastolic SR Ca2+ release appear to be important AF triggers in murine hearts (Zhang et al., 2009, 2010). Ai explores possible interactions between key Ca2+ handling proteins in such arrhythmia. These include RyR2, phospholamban, L-type Ca2+ channels (Cav1.2) (Schulman et al., 1992), and possible actions upon these of the intrinsic stress-related family of mitogen-activated protein kinase (MAPK) cascades including c-Jun N-terminal kinase, extracellular signal-regulated kinases, and p38 MAPKs whose activity alters in aging and failing hearts (Ai).
Further articles bear upon modulatory influences upon the complex of Ca2+ signaling pathways. Thus, SR Ca2+ uptake mechanisms proved affected by p21-activated kinase (Pak1) deficiency, previously identified with hypertrophic ventricular remodeling in heart failure, through altered post-transcriptional activity of key Ca2+-handling proteins, particularly SR Ca2+-ATPase (Wang et al.). Similarly, altered protein phosphatase 2A expression and activity, likely acting downstream of Pak1, may compromise responses to β-adrenergic stimulation with implications for arrhythmia and cardiac failure (Lei et al.). Finally, membrane protein regulation, trafficking and recycling are fundamental to all cellular physiological processes including those involving Ca2+ homeostasis. This prompted review of a particular, endosome-based, trafficking process, involving endocytic C-terminal Eps15 homology domain-containing regulatory proteins (Curran et al.).
Ultimately, quantitative analysis of Ca2+-mediated modulatory effects on cardiac function as a whole must extend such molecular and cellular analysis from Ca2+ homeostatic to contractile function in entire cardiac chambers (cf. Adeniran et al., 2013; Davies et al., 2014). This reconstruction will require further, more quantitative, data on the processes involved. Nevertheless, one such article succeeds in integrating abnormal Ca2+ homeostasis, ion channel and structural remodeling with ventricular electro-mechanical dynamics in the clinical problem of heart failure with preserved ejection fraction. It emerges with testable predictions of reduced systolic Ca2+ and therefore systolic force, but increased diastolic Ca2+ and therefore residual diastolic force, despite conserved ejection fraction, particularly at increased heart rates (Adeniran et al.). Simulations of this kind offer openings into more detailed and quantitative studies of sino-atrial and atrial intricacies.
Explorations of the kind described in this series of articles thus contribute to development of a systems basis for sinus node disorder (SND), atrial arrhythmia, and their translational consequences (Nattel, 2002). SND is the commonest clinical indication requiring pacemaker implantation. AF, for which available treatment is limited (Kannel and Benjamin, 2009), is a major contributor to cardiovascular morbidity and mortality, particularly in aging human populations (Juhaszova et al., 2005).
Author Contributions
CH, Drafting and planning of the editorial, response to editors report; RS, Re-reading and rewriting of the editorial; YK, Re-reading and checking of the editorial; and ML, Final corrections and rewordings, response to editors report.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
References
Adeniran, I., Hancox, J. C., and Zhang, H. (2013). In silico investigation of the short QT syndrome, using human ventricle models incorporating electromechanical coupling. Card. Electrophysiol. 4:166. doi: 10.3389/fphys.2013.00166
Baruscotti, M., Bucchi, A., Viscomi, C., Mandelli, G., Consalez, G., Gnecchi-Rusconi, T., et al. (2011). Deep bradycardia and heart block caused by inducible cardiac-specific knockout of the pacemaker channel gene Hcn4. Proc. Natl. Acad. Sci. U.S.A. 108, 1705–1710. doi: 10.1073/pnas.1010122108
Bogdanov, K. Y., Vinogradova, T. M., and Lakatta, E. G. (2001). Sinoatrial nodal cell ryanodine receptor and Na(+)-Ca(2+) exchanger: molecular partners in pacemaker regulation. Circ. Res. 88, 1254–1258. doi: 10.1161/hh1201.092095
Chandra, R., Portbury, A. L., Ray, A., Ream, M., Groelle, M., and Chikaraishi, D. M. (2006). Beta1-adrenergic receptors maintain fetal heart rate and survival. Biol. Neonate 89, 147–158. doi: 10.1159/000088842
Davies, L., Jin, J., Shen, W., Tsui, H., Shi, Y., Wang, Y., et al. (2014). Mkk4 is a negative regulator of the transforming growth factor beta 1 signaling associated with atrial remodeling and arrhythmogenesis with age. J. Am. Heart Assoc. 3, 1–19. doi: 10.1161/JAHA.113.000340
Harada, M., Luo, X., Qi, X. Y., Tadevosyan, A., Maguy, A., Ordog, B., et al. (2012). Transient receptor potential canonical-3 channel-dependent fibroblast regulation in atrial fibrillation. Circulation 126, 2051–2064. doi: 10.1161/CIRCULATIONAHA.112.121830
Harzheim, D., Pfeiffer, K. H., Fabritz, L., Kremmer, E., Buch, T., Waisman, A., et al. (2008). Cardiac pacemaker function of HCN4 channels in mice is confined to embryonic development and requires cyclic AMP. EMBO J. 27, 692–703. doi: 10.1038/emboj.2008.3
Juhaszova, M., Rabuel, C., Zorov, D. B., Lakatta, E. G., and Sollott, S. J. (2005). Protection in the aged heart: preventing the heart-break of old age? Cardiovasc. Res. 66, 233–244. doi: 10.1016/j.cardiores.2004.12.020
Kannel, W. B., and Benjamin, E. J. (2009). Current perceptions of the epidemiology of atrial fibrillation. Cardiol. Clin. 27, 13–24, vii. doi: 10.1016/j.ccl.2008.09.015
Lakatta, E. G., Maltsev, V. A., and Vinogradova, T. M. (2010). A coupled system of intracellular Ca2+ clocks and surface membrane voltage clocks controls the timekeeping mechanism of the heart's pacemaker. Circ. Res. 106, 659–673. doi: 10.1161/CIRCRESAHA.109.206078
Maltsev, V. A., and Lakatta, E. G. (2007). Normal heart rhythm is initiated and regulated by an intracellular calcium clock within pacemaker cells. Heart Lung Circ. 16, 335–348. doi: 10.1016/j.hlc.2007.07.005
Mangoni, M. E., and Nargeot, J. (2008). Genesis and regulation of the heart automaticity. Physiol. Rev. 88, 919–982. doi: 10.1152/physrev.00018.2007
Nattel, S. (2002). New ideas about atrial fibrillation 50 years on. Nature 415, 219–226. doi: 10.1038/415219a
Nattel, S., Maguy, A., Le Bouter, S., and Yeh, Y.-H. (2007). Arrhythmogenic ion-channel remodeling in the heart: heart failure, myocardial infarction, and atrial fibrillation. Physiol. Rev. 87, 425–456. doi: 10.1152/physrev.00014.2006
Rigg, L., Heath, B. M., Cui, Y., and Terrar, D. A. (2000). Localisation and functional significance of ryanodine receptors during beta-adrenoceptor stimulation in the guinea-pig sino-atrial node. Cardiovasc. Res. 48, 254–264. doi: 10.1016/S0008-6363(00)00153-X
Rigg, L., and Terrar, D. A. (1996). Possible role of calcium release from the sarcoplasmic reticulum in pacemaking in guinea-pig sino-atrial node. Exp. Physiol. 81, 877–880. doi: 10.1113/expphysiol.1996.sp003983
Sabourin, J., Antigny, F., Robin, E., Frieden, M., and Raddatz, E. (2012). Activation of transient receptor potential canonical 3 (TRPC3)-mediated Ca2+ entry by A1 adenosine receptor in cardiomyocytes disturbs atrioventricular conduction. J. Biol. Chem. 287, 26688–26701. doi: 10.1074/jbc.M112.378588
Sanders, L., Rakovic, S., Lowe, M., Mattick, P. A. D., and Terrar, D. A. (2006). Fundamental importance of Na+-Ca2+ exchange for the pacemaking mechanism in guinea-pig sino-atrial node. J. Physiol. 571, 639–649. doi: 10.1113/jphysiol.2005.100305
Schulman, H., Hanson, P. I., and Meyer, T. (1992). Decoding calcium signals by multifunctional CaM kinase. Cell Calcium 13, 401–411. doi: 10.1016/0143-4160(92)90053-U
Sohal, D. S., Nghiem, M., Crackower, M. A., Witt, S. A., Kimball, T. R., Tymitz, K. M., et al. (2001). Temporally regulated and tissue-specific gene manipulations in the adult and embryonic heart using a tamoxifen-inducible Cre protein. Circ. Res. 89, 20–25. doi: 10.1161/hh1301.092687
Stieber, J., Herrmann, S., Feil, S., Löster, J., Feil, R., Biel, M., et al. (2003). The hyperpolarization-activated channel HCN4 is required for the generation of pacemaker action potentials in the embryonic heart. Proc. Natl. Acad. Sci. U.S.A. 100, 15235–15240. doi: 10.1073/pnas.2434235100
Vinogradova, T. M., Bogdanov, K. Y., and Lakatta, E. G. (2002). beta-Adrenergic stimulation modulates ryanodine receptor Ca(2+) release during diastolic depolarization to accelerate pacemaker activity in rabbit sinoatrial nodal cells. Circ. Res. 90, 73–79. doi: 10.1161/hh0102.102271
Vinogradova, T. M., Lyashkov, A. E., Zhu, W., Ruknudin, A. M., Sirenko, S., Yang, D., et al. (2006). High basal protein kinase A-dependent phosphorylation drives rhythmic internal Ca2+ store oscillations and spontaneous beating of cardiac pacemaker cells. Circ. Res. 98, 505–514. doi: 10.1161/01.RES.0000204575.94040.d1
Vinogradova, T. M., Zhou, Y. Y., Bogdanov, K. Y., Yang, D., Kuschel, M., Cheng, H., et al. (2000). Sinoatrial node pacemaker activity requires Ca(2+)/calmodulin-dependent protein kinase II activation. Circ. Res. 87, 760–767. doi: 10.1161/01.RES.87.9.760
Vinogradova, T. M., Zhou, Y.-Y., Maltsev, V., Lyashkov, A., Stern, M., and Lakatta, E. G. (2004). Rhythmic ryanodine receptor Ca2+ releases during diastolic depolarization of sinoatrial pacemaker cells do not require membrane depolarization. Circ. Res. 94, 802–809. doi: 10.1161/01.RES.0000122045.55331.0F
Yang, H.-T., Tweedie, D., Wang, S., Guia, A., Vinogradova, T., Bogdanov, K., et al. (2002). The ryanodine receptor modulates the spontaneous beating rate of cardiomyocytes during development. Proc. Natl. Acad. Sci. U.S.A. 99, 9225–9230. doi: 10.1073/pnas.142651999
Yanni, J., Tellez, J. O., Maczewski, M., Mackiewicz, U., Beresewicz, A., Billeter, R., et al. (2011). Changes in ion channel gene expression underlying heart failure-induced sinoatrial node dysfunction. Circ. Heart Fail. 4, 496–508. doi: 10.1161/CIRCHEARTFAILURE.110.957647
Zhang, Y., Fraser, J. A., Schwiening, C., Zhang, Y., Killeen, M. J., Grace, A. A., et al. (2010). Acute atrial arrhythmogenesis in murine hearts following enhanced extracellular Ca(2+) entry depends on intracellular Ca(2+) stores. Acta Physiol. 198, 143–158. doi: 10.1111/j.1748-1716.2009.02055.x
Zhang, Y., Schwiening, C., Killeen, M. J., Zhang, Y., Ma, A., Lei, M., et al. (2009). Pharmacological changes in cellular Ca2+ homeostasis parallel initiation of atrial arrhythmogenesis in murine Langendorff-perfused hearts. Clin. Exp. Pharmacol. Physiol. 36, 969–980. doi: 10.1111/j.1440-1681.2009.05170.x
Keywords: calcium, sino-atrial node, atrial arrhythmia, Ca2+ clock, Ca2+ channels
Citation: Huang CL-H, Solaro RJ, Ke Y and Lei M (2016) Editorial: Ca2+ Signaling and Heart Rhythm. Front. Physiol. 6:423. doi: 10.3389/fphys.2015.00423
Received: 10 December 2015; Accepted: 22 December 2015;
Published: 11 January 2016.
Edited and reviewed by: Ruben Coronel, Academic Medical Center, Netherlands
Copyright © 2016 Huang, Solaro, Ke and Lei. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Christopher L.-H. Huang, clh11@cam.ac.uk