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Modulation of Ca2+ signalling in rat atrial myocytes: possible role of the α1c carboxyl terminal

Ca2+ influx through L‐type Cav1.2 (α1c) Ca2+ channels is a critical step in the activation of cardiac ryanodine receptors (RyRs) and release of Ca2+ via Ca2+‐induced Ca2+ release(CICR). The released Ca2+, in turn, is the dominant determinant of inactivation of the Ca2+ current (ICa) and termination of release. Although Ca2+ cross‐signalling is mediated by high Ca2+ fluxes in the microdomains of α1c‐RyR complexes, ICa‐gated Ca2+ cross‐signalling is surprisingly resistant to intracellular Ca2+ buffering and has steeply voltage‐dependent gain, inconsistent with a strict CICR mechanism, suggesting the existence of additional regulatory step(s). To explore the possible regulatory role of the carboxyl (C)‐terminal tail of α1c in modulating Ca2+ signalling, we tested the effects of introducing two α1c C‐terminal peptides, LA (1571–1599) and K (1617–1636) on the central α1c‐unassociated Ca2+‐release sites of atrial myocytes, using rapid (240 Hz) two‐dimensional confocal Ca2+ imaging. The frequency of spontaneously activating central sparks increased by approximately fourfold on dialysing LA‐ but not K‐peptide into myocytes voltage‐clamped at ‐80 mV. The rate but not the magnitude of caffeine (10 mM)‐triggered central Ca2+ release was significantly accelerated by LA‐ but not K‐peptide. Individual Ca2+ spark size and flux were larger in LA‐ but not in K‐peptide‐dialysed myocytes. Although LA‐peptide did not change the amplitude or inactivation kinetics of ICa, LA‐peptide did strongly enhance the central Ca2+ transients triggered by ICa at ‐30 mV (small ICa) but not at +20 mV (large ICa). In contrast, K‐peptide had no effect on either ICa or the local Ca2+ transients. LA‐peptide with a deleted calmodulin‐binding region (LM1‐peptide) had no significant effects on the central spark frequency but suppressed spontaneous spark frequency in the periphery. Our results indicate that the calmodulin‐binding LA motif of the α1c C‐terminal tail may sensitize the RyRs, thereby increasing their open probability and providing for both the voltage‐dependence of CICR and the higher frequency of spark occurrence in the periphery of atrial myocytes where the native α1c‐RyR complexes are intact.