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This Article Full Text Full Text (PDF) All Versions of this Article: 552/2/437    most recent jphysiol.2003.048330v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Woo, S.-H. Articles by Morad, M. Search for Related Content PubMed PubMed Citation Articles by Woo, S.-H. Articles by Morad, M.

Modulation of Ca²⁺ signalling in rat atrial myocytes: possible role of the _1C carboxyl terminal

Sun-Hee Woo, Nikolai M. Soldatov* and Martin Morad

Ca²⁺ influx through L-type Ca_v1.2 (_1C) 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 (I_Ca) and termination of release. Although Ca²⁺ cross-signalling is mediated by high Ca²⁺ fluxes in the microdomains of _1C-RyR complexes, I_Ca-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 _1C in modulating Ca²⁺ signalling, we tested the effects of introducing two _1C C-terminal peptides, LA (1571-1599) and K (1617-1636) on the central _1C-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 I_Ca, LA-peptide did strongly enhance the central Ca²⁺ transients triggered by I_Ca at -30 mV (small I_Ca) but not at +20 mV (large I_Ca). In contrast, K-peptide had no effect on either I_Ca 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 _1C 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 _1C-RyR complexes are intact.

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