The importance of Ca2+-dependent mechanisms for the initiation of the heartbeat

Frontiers in Physiology

Volumn 6, Issue MAR, 2015, Pages

  Capel, Rebecca A ^a   Terrar, Derek A ^a  

^a UNIVERSITY OF OXFORD   (United Kingdom)

Author keywords

Calcium clock; Cardiac; Cytosolic calcium; Membrane clock; Pacemaking; Sino atrial node

Indexed keywords

ACETYLCHOLINE; ADENYLATE CYCLASE; ADENYLATE CYCLASE 1; ADENYLATE CYCLASE 8; CALCIUM CALMODULIN DEPENDENT PROTEIN KINASE II; CALCIUM CHANNEL L TYPE; CALCIUM CHANNEL T TYPE; CALCIUM ION; CATECHOLAMINE; POTASSIUM CHANNEL; SODIUM; UNCLASSIFIED DRUG;

CALCIUM CONDUCTANCE; CALCIUM TRANSPORT; CHANNEL GATING; DIASTOLE; HEART BEAT; HEART DEPOLARIZATION; HEART MUSCLE FIBER MEMBRANE POTENTIAL; HEART MUSCLE FIBER MEMBRANE STEADY POTENTIAL; HEART RATE; HUMAN; MEMBRANE DEPOLARIZATION; NERVE STIMULATION; NONHUMAN; PARASYMPATHETIC NERVE; REVIEW; SARCOPLASMIC RETICULUM; SINUS NODE; SODIUM CALCIUM EXCHANGE; SODIUM CONDUCTANCE; SYMPATHETIC NERVE; TIME;

EID: 84926482733     PISSN: None     EISSN: 1664042X     Source Type: Journal    
DOI: 10.3389/fphys.2015.00080     Document Type: Review

References (147)

1. Baruscotti, M., Bucchi, A., and Difrancesco, D. (2005). Physiology and pharmacology of the cardiac pacemaker ("funny") current. Pharmacol. Ther. 107, 59-79. doi: 10.1016/j.pharmthera.2005.01.005
2. Baruscotti, M., and Difrancesco, D. (2004). Pacemaker channels. Ann. N.Y. Acad. Sci. 1015, 111-121. doi: 10.1196/annals.1302.009
3. Berridge, M. J. (2008). Smooth muscle cell calcium activation mechanisms. J. Physiol. 586, 5047-5061. doi: 10.1113/jphysiol.2008.160440
4. Berridge, M. J., and Galione, A. (1988). Cytosolic calcium oscillators. FASEB J. 2, 3074-3082.
5. Biel, M., Schneider, A., and Wahl, C. (2002). Cardiac HCN channels: structure, function, and modulation. Trends Cardiovasc. Med. 12, 206-212. doi: 10.1016/S1050-1738(02)00162-7
6. Biel, M., Wahl-schott, C., Michalakis, S., and Zong, X. (2009). Hyperpolarization-activated cation channels: from genes to function. Physiol. Rev. 89, 847-885. doi: 10.1152/physrev.00029.2008
7. Bogdanov, K. Y., Maltsev, V. A., Vinogradova, T. M., Lyashkov, A. E., Spurgeon, H. A., Stern, M. D., et al. (2006). Membrane potential fluctuations resulting from submembrane Ca2+ releases in rabbit sinoatrial nodal cells impart an exponential phase to the late diastolic depolarization that controls their chronotropic state. Circ. Res. 99, 979-987. doi: 10.1161/01.RES.0000247933.66532.0b
8. 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
9. Bolter, C. P., and Turner, M. J. (2009). Tertiapin-Q removes a large and rapidly acting component of vagal slowing of the guinea-pig cardiac pacemaker. Auton. Neurosci. 150, 76-81. doi: 10.1016/j.autneu.2009.05.244
10. BoSmith, R. E., Briggs, I., and Sturgess, N. C. (1993). Inhibitory actions of ZENECA ZD7288 on whole-cell hyperpolarization activated inward current (If) in guinea-pig dissociated sinoatrial node cells. Br. J. Pharmacol. 110, 343-349. doi: 10.1111/j.1476-5381.1993.tb13815.x
11. Bramich, N. J., Brock, J. A., Edwards, F. R., and Hirst, G. D. (1993). Responses to sympathetic nerve stimulation of the sinus venosus of the toad. J. Physiol. 461, 403-430. doi: 10.1113/jphysiol.1993.sp019520
12. Bramich, N. J., and Cousins, H. M. (1999). Effects of sympathetic nerve stimulation on membrane potential, [Ca2+]i, and force in the toad sinus venosus. Am. J. Physiol. 276, H115-H128.
13. Brown, H. F., McNaughton, P. A., Noble, D., and Noble, S. J. (1975). Adrenergic control of cardian pacemaker currents. Philos. Trans. R. Soc. Lond. B Biol. Sci. 270, 527-537. doi: 10.1098/rstb.1975.0029
14. Cannell, M. B., Berlin, J. R., and Lederer, W. J. (1987). Intracellular calcium in cardiac myocytes: calcium transients measured using fluorescence imaging. Soc. Gen. Physiol. Ser. 42, 201-214.
15. Capel, R. A., and Terrar, D. A. (2015). Cytosolic calcium ions exert a major influence on the firing rate and maintenance of pacemaker activity in guinea-pig sinus node. Front. Physiol. 6:23. doi: 10.3389/fphys.2015.00023
16. Chatelier, A., Renaudon, B., Bescond, J., El Chemaly, A., Demion, M., and Bois, P. (2005). Calmodulin antagonist W7 directly inhibits f-type current in rabbit sino-atrial cells. Eur. J. Pharmacol. 521, 29-33. doi: 10.1016/j.ejphar.2005.08.024
17. Chen, B., Wu, Y., Mohler, P. J., Anderson, M. E., and Song, L. S. (2009). Local control of Ca2+-induced Ca2+ release in mouse sinoatrial node cells. J. Mol. Cell. Cardiol. 47, 706-715. doi: 10.1016/j.yjmcc.2009.07.007
18. Chen, W., Wang, R., Chen, B., Zhong, X., Kong, H., Bai, Y., et al. (2014). The ryanodine receptor store-sensing gate controls Ca2+ waves and Ca2+-triggered arrhythmias. Nat. Med. 20, 184-192. doi: 10.1038/nm.3440
19. Chen, W. T., Chen, Y. C., Lu, Y. Y., Kao, Y. H., Huang, J. H., Lin, Y. K., et al. (2013). Apamin modulates electrophysiological characteristics of the pulmonary vein and the Sinoatrial Node. Eur. J. Clin. Invest. 43, 957-963. doi: 10.1111/eci.12125
20. Cho, C. H., Kim, S. S., Jeong, M. J., Lee, C. O., and Shin, H. S. (2000). The Na+ -Ca2+ exchanger is essential for embryonic heart development in mice. Mol. Cells 10, 712-722. doi: 10.1007/s100590000034
21. Choate, J. K., Edwards, F. R., Hirst, G. D., and O'Shea, J. E. (1993). Effects of sympathetic nerve stimulation on the sino-atrial node of the guinea-pig. J. Physiol. 471, 707-727. doi: 10.1113/jphysiol.1993.sp019924
22. Christel, C. J., Cardona, N., Mesirca, P., Herrmann, S., Hofmann, F., Striessnig, J., et al. (2012). Distinct localization and modulation of Cav1.2 and Cav1.3 L-type Ca2+ channels in mouse sinoatrial node. J. Physiol. 590, 6327-6342. doi: 10.1113/jphysiol.2012.239954
23. Clark, R. B., Mangoni, M. E., Lueger, A., Couette, B., Nargeot, J., and Giles, W. R. (2004). A rapidly activating delayed rectifier K+ current regulates pacemaker activity in adult mouse sinoatrial node cells. Am. J. Physiol. Heart Circ. Physiol. 286, H1757-H1766. doi: 10.1152/ajpheart.00753.2003
24. Collins, T. P., and Terrar, D. A. (2012). Ca(2+)-stimulated adenylyl cyclases regulate the L-type Ca(2+) current in guinea-pig atrial myocytes. J. Physiol. 590, 1881-1893. doi: 10.1113/jphysiol.2011.227066
25. Coppen, S. R., Kodama, I., Boyett, M. R., Dobrzynski, H., Takagishi, Y., Honjo, H., et al. (1999). Connexin45, a major connexin of the rabbit sinoatrial node, is co-expressed with connexin43 in a restricted zone at the nodal-crista terminalis border. J. Histochem. Cytochem. 47, 907-918. doi: 10.1177/002215549904700708
26. Denyer, J. C., and Brown, H. F. (1990). Pacemaking in rabbit isolated sino-atrial node cells during Cs+ block of the hyperpolarization-activated current if. J. Physiol. 429, 401-409. doi: 10.1113/jphysiol.1990.sp018264
27. DiFrancesco, D. (2010). The role of the funny current in pacemaker activity. Circ. Res. 106, 434-446. doi: 10.1161/CIRCRESAHA.109.208041
28. DiFrancesco, D., and Mangoni, M. (1994). Modulation of single hyperpolarization-activated channels (i(f)) by cAMP in the rabbit sino-atrial node. J. Physiol. 474, 473-482. doi: 10.1113/jphysiol.1994.sp020038
29. DiFrancesco, D., and Noble, D. (2012a). The funny current has a major pacemaking role in the sinus node. Heart Rhythm 9, 299-301. doi: 10.1016/j.hrthm.2011.09.021
30. DiFrancesco, D., and Noble, D. (2012b). Rebuttal: "The funny current in the context of the coupled clock pacemaker cell system." Heart Rhythm 9, 457-458. doi: 10.1016/j.hrthm.2011.09.023
31. Dobrzynski, H., Boyett, M. R., and Anderson, R. H. (2007). New insights into pacemaker activity: promoting understanding of sick sinus syndrome. Circulation 115, 1921-1932. doi: 10.1161/CIRCULATIONAHA.106.616011
32. Fenske, S., Krause, S. C., Hassan, S. I., Becirovic, E., Auer, F., Bernard, R., et al. (2013). Sick sinus syndrome in HCN1-deficient mice. Circulation 128, 2585-2594. doi: 10.1161/CIRCULATIONAHA.113.003712
33. Fischmeister, R., and Hartzell, H. C. (1986). Mechanism of action of acetylcholine on calcium current in single cells from frog ventricle. J. Physiol. 376, 183-202. doi: 10.1113/jphysiol.1986.sp016148
34. Fischmeister, R., and Shrier, A. (1989). Interactive effects of isoprenaline, forskolin and acetylcholine on Ca2+ current in frog ventricular myocytes. J. Physiol. 417, 213-239. doi: 10.1113/jphysiol.1989.sp017798
35. Gao, Z., Rasmussen, T. P., Li, Y., Kutschke, W., Koval, O. M., Wu, Y., et al. (2013). Genetic inhibition of Na+-Ca2+ exchanger current disables fight or flight sinoatrial node activity without affecting resting heart rate. Circ. Res. 112, 309-317. doi: 10.1161/CIRCRESAHA.111.300193
36. Gao, Z., Singh, M. V., Hall, D. D., Koval, O. M., Luczak, E. D., Joiner, M. L., et al. (2011). Catecholamine-independent heart rate increases require Ca2+/calmodulin-dependent protein kinase II. Circ. Arrhythm. Electrophysiol. 4, 379-387. doi: 10.1161/CIRCEP.110.961771
37. Glukhov, A. V., Kalyanasundaram, A., Lou, Q., Hage, L. T., Hansen, B. J., Belevych, A. E., et al. (2015). Calsequestrin 2 deletion causes sinoatrial node dysfunction and atrial arrhythmias associated with altered sarcoplasmic reticulum calcium cycling and degenerative fibrosis within the mouse atrial pacemaker complex. Eur. Heart J. 36, 686-697. doi: 10.1093/eurheartj/eht452
38. Groenke, S., Larson, E. D., Alber, S., Zhang, R., Lamp, S. T., Ren, X., et al. (2013). Complete atrial-specific knockout of sodium-calcium exchange eliminates sinoatrial node pacemaker activity. PLoS ONE 8:e81633. doi: 10.1371/journal.pone.0081633
39. Hagiwara, N., and Irisawa, H. (1989). Modulation by intracellular Ca2+ of the hyperpolarization-activated inward current in rabbit single sino-atrial node cells. J. Physiol. 409, 121-141. doi: 10.1113/jphysiol.1989.sp017488
40. Hagiwara, N., Irisawa, H., and Kameyama, M. (1998). Contribution of two types of calcium currents to the pacemaker potentials of rabbit sino-atrial node cells. J. Physiol. 395, 233-253.
41. Hagiwara, N., Irisawa, H., Kasanuki, H., and Hosoda, S. (1992). Background current in sino-atrial node cells of the rabbit heart. J. Physiol. 448, 53-72. doi: 10.1113/jphysiol.1992.sp019029
42. Han, X., Shimoni, Y., and Giles, W. R. (1995). A cellular mechanism for nitric oxide-mediated cholinergic control of mammalian heart rate. J. Gen. Physiol. 106, 45-65. doi: 10.1085/jgp.106.1.45
43. Hauswirth, O., Noble, D., and Tsien, R. W. (1968). Adrenaline: mechanism of action on the pacemaker potential in cardiac Purkinje fibers. Science 162, 916-917. doi: 10.1126/science.162.3856.916
44. He, C., Chen, F., Li, B., and Hu, Z. (2014). Neurophysiology of HCN channels: from cellular functions to multiple regulations. Prog. Neurobiol. 112, 1-23. doi: 10.1016/j.pneurobio.2013.10.001
45. Heath, B. M., and Terrar, D. A. (2000). Protein kinase C enhances the rapidly activating delayed rectifier potassium current, IKr, through a reduction in C-type inactivation in guinea-pig ventricular myocytes. J. Physiol. 522(Pt 3), 391-402. doi: 10.1111/j.1469-7793.2000.t01-2-00391.x
46. Herring, N. (2014). Autonomic control of the heart: going beyond the classical neurotransmitters. Exp. Physiol. doi: 10.1113/expphysiol.2014.080184. [Epub ahead of print].
47. Herrmann, S., Lipp, P., Wiesen, K., Stieber, J., Nguyen, H., Kaiser, E., et al. (2013). The cardiac sodium-calcium exchanger NCX1 is a key player in the initiation and maintenance of a stable heart rhythm. Cardiovasc. Res. 99, 780-788. doi: 10.1093/cvr/cvt154
48. Hescheler, J., Kameyama, M., and Trautwein, W. (1986). On the mechanism of muscarinic inhibition of the cardiac Ca current. Pflugers Arch. 407, 182-189. doi: 10.1007/BF00580674
49. Himeno, Y., Toyoda, F., Satoh, H., Amano, A., Cha, C. Y., Matsuura, H., et al. (2011). Minor contribution of cytosolic Ca2+ transients to the pacemaker rhythm in guinea pig sinoatrial node cells. Am. J. Physiol. Heart Circ. Physiol. 300, H251-H261. doi: 10.1152/ajpheart.00764.2010
50. Hof, T., Simard, C., Rouet, R., Salle, L., and Guinamard, R. (2013). Implication of the TRPM4 nonselective cation channel in mammalian sinus rhythm. Heart Rhythm 10, 1683-1689. doi: 10.1016/j.hrthm.2013.08.014
51. Hua, R., Adamczyk, A., Robbins, C., Ray, G., and Rose, R. A. (2012). Distinct patterns of constitutive phosphodiesterase activity in mouse sinoatrial node and atrial myocardium. PLoS ONE 7:e47652. doi: 10.1371/journal.pone.0047652
52. Huang, Z. M., Prasad, C., Britton, F. C., Ye, L. L., Hatton, W. J., and Duan, D. (2009). Functional role of CLC-2 chloride inward rectifier channels in cardiac sinoatrial nodal pacemaker cells. J. Mol. Cell. Cardiol. 47, 121-132. doi: 10.1016/j.yjmcc.2009.04.008
53. Huser, J., Blatter, L. A., and Lipsius, S. L. (2000). Intracellular Ca2+ release contributes to automaticity in cat atrial pacemaker cells. J. Physiol. 524(Pt 2), 415-422. doi: 10.1111/j.1469-7793.2000.00415.x
54. Imlach, W. L., Finch, S. C., Miller, J. H., Meredith, A. L., and Dalziel, J. E. (2010). A role for BK channels in heart rate regulation in rodents. PLoS ONE 5:e8698. doi: 10.1371/journal.pone.0008698
55. Imtiaz, M. S. (2012). Calcium oscillations and pacemaking. Adv. Exp. Med. Biol. 740, 511-520. doi: 10.1007/978-94-007-2888-2_22
56. Imtiaz, M. S., Katnik, C. P., Smith, D. W., and van Helden, D. F. (2006). Role of voltage-dependent modulation of store Ca2+ release in synchronization of Ca2+ oscillations. Biophys. J. 90, 1-23. doi: 10.1529/biophysj.104.058743
57. Imtiaz, M. S., von der Weid, P. Y., Laver, D. R., and van Helden, D. F. (2010). SR Ca2+ store refill-a key factor in cardiac pacemaking. J. Mol. Cell. Cardiol. 49, 412-426. doi: 10.1016/j.yjmcc.2010.03.015
58. Imtiaz, M. S., Zhao, J., Hosaka, K., von der Weid, P. Y., Crowe, M., and van Helden, D. F. (2007). Pacemaking through Ca2+ stores interacting as coupled oscillators via membrane depolarization. Biophys. J. 92, 3843-3861. doi: 10.1529/biophysj.106.095687
59. Irisawa, H. (1978). Comparative physiology of the cardiac pacemaker mechanism. Physiol. Rev. 58, 461-498.
60. Irisawa, H., Brown, H. F., and Giles, W. (1993). Cardiac pacemaking in the sinoatrial node. Physiol. Rev. 73, 197-227.
61. Ito, H., Ono, K., and Noma, A. (1994). Background conductance attributable to spontaneous opening of muscarinic K+ channels in rabbit sino-atrial node cells. J. Physiol. 476, 55-68.
62. Jackson, V. M., Rakovic, S., and Terrar, D. A. (2002). Effects of isoproterenol on calcium transients and calcium sparks in guinea-pig sino-atrial node cells imaged by confocal microscopy. Biophys. J. 82, 648A.
63. Ju, Y. K., and Allen, D. G. (1998). Intracellular calcium and Na+-Ca2+ exchange current in isolated toad pacemaker cells. J. Physiol. 508(Pt 1), 153-166. doi: 10.1111/j.1469-7793.1998.153br.x
64. Ju, Y. K., and Allen, D. G. (2007). Store-operated Ca2+ entry and TRPC expression; possible roles in cardiac pacemaker tissue. Heart Lung Circ. 16, 349-355. doi: 10.1016/j.hlc.2007.07.004
65. Ju, Y. K., Liu, J., Lee, B. H., Lai, D., Woodcock, E. A., Lei, M., et al. (2011). Distribution and functional role of inositol 1,4,5-trisphosphate receptors in mouse sinoatrial node. Circ. Res. 109, 848-857. doi: 10.1161/CIRCRESAHA.111.243824
66. Kang, T. M., and Hilgemann, D. W. (2004). Multiple transport modes of the cardiac Na+/Ca2+ exchanger. Nature 427, 544-548. doi: 10.1038/nature02271
67. Ke, Y., Lei, M., Collins, T. P., Rakovic, S., Mattick, P. A., Yamasaki, M., et al. (2007). Regulation of L-type calcium channel and delayed rectifier potassium channel activity by p21-activated kinase-1 in guinea pig sinoatrial node pacemaker cells. Circ. Res. 100, 1317-1327. doi: 10.1161/01.RES.0000266742.51389.a4
68. Kodama, I., Nikmaram, M. R., Boyett, M. R., Suzuki, R., Honjo, H., and Owen, J. M. (1997). Regional differences in the role of the Ca2+ and Na+ currents in pacemaker activity in the sinoatrial node. Am. J. Physiol. 272, H2793-H2806.
69. Koushik, S. V., Wang, J., Rogers, R., Moskophidis, D., Lambert, N. A., Creazzo, T. L., et al. (2001). Targeted inactivation of the sodium-calcium exchanger (Ncx1) results in the lack of a heartbeat and abnormal myofibrillar organization. FASEB J. 15, 1209-1211. doi: 10.1096/fj.00-0696fje
70. Kryukova, Y. N., Protas, L., and Robinson, R. B. (2012). Ca2+-activated adenylyl cyclase 1 introduces Ca2+-dependence to beta-adrenergic stimulation of HCN2 current. J. Mol. Cell. Cardiol. 52, 1233-1239. doi: 10.1016/j.yjmcc.2012.03.010
71. Lai, M. H., Wu, Y., Gao, Z., Anderson, M. E., Dalziel, J. E., and Meredith, A. L. (2014). BK channels regulate sinoatrial node firing rate and cardiac pacing in vivo. Am. J. Physiol. Heart Circ. Physiol. 307, H1327-H1338. doi: 10.1152/ajpheart.00354.2014
72. Lakatta, E. G., and DiFrancesco, D. (2009). What keeps us ticking: a funny current, a calcium clock, or both? J. Mol. Cell. Cardiol. 47, 157-170. doi: 10.1016/j.yjmcc.2009.03.022
73. Lakatta, E. G., and Maltsev, V. A. (2012). Rebuttal: what I(f) the shoe doesn't fit? "The funny current has a major pacemaking role in the sinus node." Heart Rhythm 9, 459-460. doi: 10.1016/j.hrthm.2011.09.024
74. Lei, M., and Brown, H. F. (1996). Two components of the delayed rectifier potassium current, IK, in rabbit sino-atrial node cells. Exp. Physiol. 81, 725-741. doi: 10.1113/expphysiol.1996.sp003972
75. Lei, M., Honjo, H., Kodama, I., and Boyett, M. R. (2001). Heterogeneous expression of the delayed-rectifier K+ currents i(K,r) and i(K,s) in rabbit sinoatrial node cells. J. Physiol. 535, 703-714. doi: 10.1111/j.1469-7793.2001.t01-1-00703.x
76. Liu, J., Xin, L., Benson, V. L., Allen, D. G., and Ju, Y. K. (2015). Store-operated calcium entry and the localization of STIM1 and Orai1 proteins in isolated mouse sinoatrial node cells. Front. Physiol. 6:69. doi: 10.3389/fphys.2015.00069
77. Lyashkov, A. E., Vinogradova, T. M., Zahanich, I., Li, Y., Younes, A., Nuss, H. B., et al. (2009). Cholinergic receptor signaling modulates spontaneous firing of sinoatrial nodal cells via integrated effects on PKA-dependent Ca(2+) cycling and I(KACh). Am. J. Physiol. Heart Circ. Physiol. 297, H949-H959. doi: 10.1152/ajpheart.01340.2008
78. Maltsev, A. V., Yaniv, Y., Stern, M. D., Lakatta, E. G., and Maltsev, V. A. (2013). RyR-NCX-SERCA local cross-talk ensures pacemaker cell function at rest and during the fight-or-flight reflex. Circ. Res. 113, e94-e100. doi: 10.1161/CIRCRESAHA.113.302465
79. Maltsev, V. A., and Lakatta, E. G. (2012). The funny current in the context of the coupled-clock pacemaker cell system. Heart Rhythm 9, 302-307. doi: 10.1016/j.hrthm.2011.09.022
80. Maltsev, V. A., Vinogradova, T. M., Stern, M. D., and Lakatta, E. G. (2011). 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. 300, H2323-H2324; author reply H2325-H2326. doi: 10.1152/ajpheart.00110.2011
81. Maltsev, V. A., Yaniv, Y., Maltsev, A. V., Stern, M. D., and Lakatta, E. G. (2014). Modern perspectives on numerical modeling of cardiac pacemaker cell. J. Pharmacol. Sci. 125, 6-38. doi: 10.1254/jphs.13R04CR
82. Mangoni, M. E., Couette, B., Bourinet, E., Platzer, J., Reimer, D., Striessnig, J., et al. (2003). Functional role of L-type Cav1.3 Ca2+ channels in cardiac pacemaker activity. Proc. Natl. Acad. Sci. U.S.A. 100, 5543-5548. doi: 10.1073/pnas.0935295100
83. Mangoni, M. E., Couette, B., Marger, L., Bourinet, E., Striessnig, J., and Nargeot, J. (2006a). Voltage-dependent calcium channels and cardiac pacemaker activity: from ionic currents to genes. Prog. Biophys. Mol. Biol. 90, 38-63. doi: 10.1016/j.pbiomolbio.2005.05.003
84. 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
85. Mangoni, M. E., Traboulsie, A., Leoni, A. L., Couette, B., Marger, L., Le Quang, K., et al. (2006b). Bradycardia and slowing of the atrioventricular conduction in mice lacking CaV3.1/alpha1G T-type calcium channels. Circ. Res. 98, 1422-1430. doi: 10.1161/01.RES.0000225862.14314.49
86. Maruyama, M., Xiao, J., Zhou, Q., Vembaiyan, K., Chua, S. K., Rubart-Von Der Lohe, M., et al. (2013). Carvedilol analogue inhibits triggered activities evoked by both early and delayed afterdepolarizations. Heart Rhythm 10, 101-107. doi: 10.1016/j.hrthm.2012.09.006
87. Mattick, P., Parrington, J., Odia, E., Simpson, A., Collins, T., and Terrar, D. (2007). Ca2+-stimulated adenylyl cyclase isoform AC1 is preferentially expressed in guinea-pig sino-atrial node cells and modulates the I(f) pacemaker current. J. Physiol. 582, 1195-1203. doi: 10.1113/jphysiol.2007.133439
88. McHale, N., Hollywood, M., Sergeant, G., and Thornbury, K. (2006). Origin of spontaneous rhythmicity in smooth muscle. J. Physiol. 570, 23-28. doi: 10.1113/jphysiol.2005.098376
89. Mesirca, P., Alig, J., Torrente, A. G., Muller, J. C., Marger, L., Rollin, A., et al. (2014a). Cardiac arrhythmia induced by genetic silencing of 'funny' (f) channels is rescued by GIRK4 inactivation. Nat. Commun. 5, 4664. doi: 10.1038/ncomms5664
90. Mesirca, P., Torrente, A. G., and Mangoni, M. E. (2014b). T-type channels in the sino-atrial and atrioventricular pacemaker mechanism. Pflugers Arch. 466, 791-799. doi: 10.1007/s00424-014-1482-6
91. Miake, J., Marban, E., and Nuss, H. B. (2002). Biological pacemaker created by gene transfer. Nature 419, 132-133. doi: 10.1038/419132b
92. Mitsuiye, T., Guo, J., and Noma, A. (1999). Nicardipine-sensitive Na+-mediated single channel currents in guinea-pig sinoatrial node pacemaker cells. J. Physiol. 521(Pt 1), 69-79. doi: 10.1111/j.1469-7793.1999.00069.x
93. Mitsuiye, T., Shinagawa, Y., and Noma, A. (2000). Sustained inward current during pacemaker depolarization in mammalian sinoatrial node cells. Circ. Res. 87, 88-91. doi: 10.1161/01.RES.87.2.88
94. Musialek, P., Rigg, L., Terrar, D. A., Paterson, D. J., and Casadei, B. (2000). Role of cGMP-inhibited phosphodiesterase and sarcoplasmic calcium in mediating the increase in basal heart rate with nitric oxide donors. J. Mol. Cell. Cardiol. 32, 1831-1840. doi: 10.1006/jmcc.2000.1216
95. Neco, P., Torrente, A. G., Mesirca, P., Zorio, E., Liu, N., Priori, S. G., et al. (2012). Paradoxical effect of increased diastolic Ca(2+) release and decreased sinoatrial node activity in a mouse model of catecholaminergic polymorphic ventricular tachycardia. Circulation 126, 392-401. doi: 10.1161/CIRCULATIONAHA.111.075382
96. Noble, D., Denyer, J. C., Brown, H. F., and Difrancesco, D. (1992). Reciprocal role of the inward currents ib, Na and i(f) in controlling and stabilizing pacemaker frequency of rabbit sino-atrial node cells. Proc. Biol. Sci. 250, 199-207. doi: 10.1098/rspb.1992.0150
97. Noma, A. (1996). Ionic mechanisms of the cardiac pacemaker potential. Jpn. Heart J. 37, 673-682. doi: 10.1536/ihj.37.673
98. Noma, A., and Irisawa, H. (1975). Effects of Na+ and K+ on the resting membrane potential of the rabbit sinoatrial node cell. Jpn. J. Physiol. 25, 207-302. doi: 10.2170/jjphysiol.25.287
99. Noma, A., Nakayama, T., Kurachi, Y., and Irisawa, H. (1984). Resting K conductances in pacemaker and non-pacemaker heart cells of the rabbit. Jpn. J. Physiol. 34, 245-254. doi: 10.2170/jjphysiol.34.245
100. Ottolia, M., Torres, N., Bridge, J. H., Philipson, K. D., and Goldhaber, J. I. (2013). Na/Ca exchange and contraction of the heart. J. Mol. Cell. Cardiol. 61, 28-33. doi: 10.1016/j.yjmcc.2013.06.001
101. Petit-Jacques, J., Bois, P., Bescond, J., and Lenfant, J. (1993). Mechanism of muscarinic control of the high-threshold calcium current in rabbit sino-atrial node myocytes. Pflugers Arch. 423, 21-27. doi: 10.1007/BF00374956
102. Proenza, C., Angoli, D., Agranovich, E., Macri, V., and Accili, E. A. (2002). Pacemaker channels produce an instantaneous current. J. Biol. Chem. 277, 5101-5109. doi: 10.1074/jbc.M106974200
103. Rakovic, S., Rigg, L., Ishida, H., and Terrar, D. A. (2001). Calcium transients in guinea-pig sino-atrial node cells imaged by confocal microscopy. Biophys. J. 80, 350A.
104. Reuter, H., Henderson, S. A., Han, T., Ross, R. S., Goldhaber, J. I., and Philipson, K. D. (2002). The Na+-Ca2+ exchanger is essential for the action of cardiac glycosides. Circ. Res. 90, 305-308. doi: 10.1161/hh0302.104562
105. 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
106. Rigg, L., Mattick, P. A., Heath, B. M., and Terrar, D. A. (2003). Modulation of the hyperpolarization-activated current (I(f)) by calcium and calmodulin in the guinea-pig sino-atrial node. Cardiovasc. Res. 57, 497-504. doi: 10.1016/S0008-6363(02)00668-5
107. 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
108. Sah, R., Mesirca, P., Van den Boogert, M., Rosen, J., Mably, J., Mangoni, M. E., et al. (2013). Ion channel-kinase TRPM7 is required for maintaining cardiac automaticity. Proc. Natl. Acad. Sci. U.S.A. 110, E3037-E3046. doi: 10.1073/pnas.1311865110
109. Sanders, L., Rakovic, S., Lowe, M., Mattick, P. A., 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
110. Schaub, M. C., Hefti, M. A., and Zaugg, M. (2006). Integration of calcium with the signaling network in cardiac myocytes. J. Mol. Cell. Cardiol. 41, 183-214. doi: 10.1016/j.yjmcc.2006.04.005
111. Seyama, I. (1979). Characteristics of the anion channel in the sino-atrial node cell of the rabbit. J. Physiol. 294, 447-460. doi: 10.1113/jphysiol.1979.sp012940
112. Shibata, E. F., and Giles, W. R. (1985). Ionic currents that generate the spontaneous diastolic depolarization in individual cardiac pacemaker cells. Proc. Natl. Acad. Sci. U.S.A. 82, 7796-7800. doi: 10.1073/pnas.82.22.7796
113. Shinohara, T., Kim, D., Joung, B., Maruyama, M., Vembaiyan, K., Back, T. G., et al. (2014). Carvedilol analog modulates both basal and stimulated sinoatrial node automaticity. Heart Vessels 29, 396-403. doi: 10.1007/s00380-013-0378-2
114. Sitsapesan, R., and Williams, A. J. (1994). Regulation of the gating of the sheep cardiac sarcoplasmic reticulum Ca(2+)-release channel by luminal Ca2+. J. Membr. Biol. 137, 215-226. doi: 10.1007/BF00232590
115. Sitsapesan, R., and Williams, A. J. (1997). Regulation of current flow through ryanodine receptors by luminal Ca2+. J. Membr. Biol. 159, 179-185. doi: 10.1007/s002329900281
116. Tang, Q., Jin, M. W., Xiang, J. Z., Dong, M. Q., Sun, H. Y., Lau, C. P., et al. (2007). The membrane permeable calcium chelator BAPTA-AM directly blocks human ether a-go-go-related gene potassium channels stably expressed in HEK 293 cells. Biochem. Pharmacol. 74, 1596-1607. doi: 10.1016/j.bcp.2007.07.042
117. ten Velde, I., de Jonge, B., Verheijck, E. E., van Kempen, M. J., Analbers, L., Gros, D., et al. (1995). Spatial distribution of connexin43, the major cardiac gap junction protein, visualizes the cellular network for impulse propagation from sinoatrial node to atrium. Circ. Res. 76, 802-811. doi: 10.1161/01.RES.76.5.802
118. van Borren, M. M., Verkerk, A. O., Wilders, R., Hajji, N., Zegers, J. G., Bourier, J., et al. (2010). Effects of muscarinic receptor stimulation on Ca2+ transient, cAMP production and pacemaker frequency of rabbit sinoatrial node cells. Basic Res. Cardiol. 105, 73-87. doi: 10.1007/s00395-009-0048-9
119. Verheijck, E. E., van Ginneken, A. C., Bourier, J., and Bouman, L. N. (1995). Effects of delayed rectifier current blockade by E-4031 on impulse generation in single sinoatrial nodal myocytes of the rabbit. Circ. Res. 76, 607-615. doi: 10.1161/01.RES.76.4.607
120. Verkerk, A. O., and Wilders, R. (2013). Hyperpolarization-activated current, If, in mathematical models of rabbit sinoatrial node pacemaker cells. Biomed Res. Int. 2013, 872454. doi: 10.1155/2013/872454
121. Verkerk, A. O., Wilders, R., Zegers, J. G., van Borren, M. M., Ravesloot, J. H., and Verheijck, E. E. (2002). Ca(2+)-activated Cl(-) current in rabbit sinoatrial node cells. J. Physiol. 540, 105-117. doi: 10.1113/jphysiol.2001.013184
122. Vinogradova, T. M., Bogdanov, K. Y., and Lakatta, E. G. (2002a). 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
123. Vinogradova, T. M., Bogdanov, K. Y., and Lakatta, E. G. (2002b). Novel perspectives on the beating rate of the heart. Circ. Res. 91, e3. doi: 10.1161/01.RES.0000031164.28289.55
124. Vinogradova, T. M., Brochet, D. X., Sirenko, S., Li, Y., Spurgeon, H., and Lakatta, E. G. (2010). Sarcoplasmic reticulum Ca2+ pumping kinetics regulates timing of local Ca2+ releases and spontaneous beating rate of rabbit sinoatrial node pacemaker cells. Circ. Res. 107, 767-775. doi: 10.1161/CIRCRESAHA.110.220517
125. Vinogradova, T. M., and Lakatta, E. G. (2009). Regulation of basal and reserve cardiac pacemaker function by interactions of cAMP-mediated PKA-dependent Ca2+ cycling with surface membrane channels. J. Mol. Cell. Cardiol. 47, 456-474. doi: 10.1016/j.yjmcc.2009.06.014
126. 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
127. Vinogradova, T. M., Maltsev, V. A., Bogdanov, K. Y., Lyashkov, A. E., and Lakatta, E. G. (2005). Rhythmic Ca2+ oscillations drive sinoatrial nodal cell pacemaker function to make the heart tick. Ann. N.Y. Acad. Sci. 1047, 138-156. doi: 10.1196/annals.1341.013
128. Vinogradova, T. M., Sirenko, S., Lyashkov, A. E., Younes, A., Li, Y., Zhu, W., et al. (2008). Constitutive phosphodiesterase activity restricts spontaneous beating rate of cardiac pacemaker cells by suppressing local Ca2+ releases. Circ. Res. 102, 761-769. doi: 10.1161/CIRCRESAHA.107.161679
129. 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
130. 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
131. Wahl-Schott, C., Fenske, S., and Biel, M. (2014). HCN channels: new roles in sinoatrial node function. Curr. Opin. Pharmacol. 15, 83-90. doi: 10.1016/j.coph.2013.12.005
132. Wainger, B. J., Degennaro, M., Santoro, B., Siegelbaum, S. A., and Tibbs, G. R. (2001). Molecular mechanism of cAMP modulation of HCN pacemaker channels. Nature 411, 805-810. doi: 10.1038/35081088
133. Wang, Y., Tsui, H., Ke, Y., Shi, Y., Li, Y., Davies, L., et al. (2014). Pak1 is required to maintain ventricular Ca(2)(+) homeostasis and electrophysiological stability through SERCA2a regulation in mice. Circ. Arrhythm. Electrophysiol. 7, 938-948. doi: 10.1161/CIRCEP.113.001198
134. Wu, Y., and Anderson, M. E. (2014). CaMKII in sinoatrial node physiology and dysfunction. Front. Pharmacol. 5:48. doi: 10.3389/fphar.2014.00048
135. Wu, Y., Gao, Z., Chen, B., Koval, O. M., Singh, M. V., Guan, X., et al. (2009). Calmodulin kinase II is required for fight or flight sinoatrial node physiology. Proc. Natl. Acad. Sci. U.S.A. 106, 5972-5977. doi: 10.1073/pnas.0806422106
136. Xie, Y., Ding, W. G., and Matsuura, H. (2015). Ca2+/calmodulin potentiates I Ks in sinoatrial node cells by activating Ca2+/calmodulin-dependent protein kinase II. Pflugers Arch. 467, 241-251. doi: 10.1007/s00424-014-1507-1
137. Yaniv, Y., Maltsev, V. A., Escobar, A. L., Spurgeon, H. A., Ziman, B. D., Stern, M. D., et al. (2011). Beat-to-beat Ca(2+)-dependent regulation of sinoatrial nodal pacemaker cell rate and rhythm. J. Mol. Cell. Cardiol. 51, 902-905. doi: 10.1016/j.yjmcc.2011.08.029
138. Yaniv, Y., Stern, M. D., Lakatta, E. G., and Maltsev, V. A. (2013). Mechanisms of beat-to-beat regulation of cardiac pacemaker cell function by Ca(2)(+) cycling dynamics. Biophys. J. 105, 1551-1561. doi: 10.1016/j.bpj.2013.08.024
139. Yoo, S., Lee, S. H., Choi, B. H., Yeom, J. B., Ho, W. K., and Earm, Y. E. (1998). Dual effect of nitric oxide on the hyperpolarization-activated inward current (I(f)) in sino-atrial node cells of the rabbit. J. Mol. Cell. Cardiol. 30, 2729-2738. doi: 10.1006/jmcc.1998.0845
140. Younes, A., Lyashkov, A. E., Graham, D., Sheydina, A., Volkova, M. V., Mitsak, M., et al. (2008). Ca(2+) -stimulated basal adenylyl cyclase activity localization in membrane lipid microdomains of cardiac sinoatrial nodal pacemaker cells. J. Biol. Chem. 283, 14461-14468. doi: 10.1074/jbc.M707540200
141. Yuill, K. H., and Hancox, J. C. (2002). Characteristics of single cells isolated from the atrioventricular node of the adult guinea-pig heart. Pflugers Arch. 445, 311-320. doi: 10.1007/s00424-002-0932-8
142. Zaza, A., Maccaferri, G., Mangoni, M., and Difrancesco, D. (1991). Intracellular calcium does not directly modulate cardiac pacemaker (if) channels. Pflugers Arch. 419, 662-664. doi: 10.1007/BF00370312
143. Zaza, A., Micheletti, M., Brioschi, A., and Rocchetti, M. (1997). Ionic currents during sustained pacemaker activity in rabbit sino-atrial myocytes. J. Physiol. 505(Pt 3), 677-688. doi: 10.1111/j.1469-7793.1997.677ba.x
144. Zhang, H., Butters, T., Adeniran, I., Higham, J., Holden, A. V., Boyett, M. R., et al. (2012). Modeling the chronotropic effect of isoprenaline on rabbit sinoatrial node. Front. Physiol. 3:241. doi: 10.3389/fphys.2012.00241
145. Zhang, Y. H., and Hancox, J. C. (2009). Regulation of cardiac Na+-Ca2+ exchanger activity by protein kinase phosphorylation-still a paradox? Cell Calcium 45, 1-10. doi: 10.1016/j.ceca.2008.05.005
146. Zhang, Z., Xu, Y., Song, H., Rodriguez, J., Tuteja, D., Namkung, Y., et al. (2002). Functional Roles of Ca(v)1.3 (alpha(1D)) calcium channel in sinoatrial nodes: insight gained using gene-targeted null mutant mice. Circ. Res. 90, 981-987. doi: 10.1161/01.RES.0000018003.14304.E2
147. Zhou, Q., Xiao, J., Jiang, D., Wang, R., Vembaiyan, K., Wang, A., et al. (2011). Carvedilol and its new analogs suppress arrhythmogenic store overload-induced Ca2+ release. Nat. Med. 17, 1003-1009. doi: 10.1038/nm.2406