期刊
CARDIOVASCULAR RESEARCH
卷 109, 期 3, 页码 451-461出版社
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvw006
关键词
Pacemaker activity; Sino-atrial node; Ca2+ dynamics; Ca(v)1.3; L-type Ca2+ channels
资金
- Agence Nationale de la Recherche [2010-BLAN-1128-01, 13-BSV1-0023, 11-LABX-0015, 10-LABX-33]
- Austrian Science Fund (FWF) [F44020]
- European Research Programme CavNet (6FP) [MRTN-CT-2006-035367]
- Fondation pour la Recherche Medicale postdoctoral fellowship
Sino-atrial node (SAN) automaticity is an essential mechanism of heart rate generation that is still not completely understood. Recent studies highlighted the importance of intracellular Ca2+ ([Ca2+](i)) dynamics during SAN pacemaker activity. Nevertheless, the functional role of voltage-dependent L-type Ca2+ channels in controlling SAN [Ca2+](i) release is largely unexplored. Since Ca(v)1.3 is the predominant L-type Ca2+ channel isoform in SAN cells, we studied [Ca2+](i) dynamics in isolated cells and ex vivo SAN preparations explanted from wild-type (WT) and Ca(v)1.3 knockout (KO) mice (Ca(v)1.3(-/-)). We found that Ca(v)1.3 deficiency strongly impaired [Ca2+](i) dynamics, reducing the frequency of local [Ca2+](i) release events and preventing their synchronization. This impairment inhibited the generation of Ca2+ transients and delayed spontaneous activity. We also used action potentials recorded in WT SAN cells as voltage-clamp commands for Ca(v)1.3(-/-) cells. Although these experiments showed abolished Ca2+ entry through L-type Ca2+ channels in the diastolic depolarization range of KO SAN cells, their sarcoplasmic reticulum Ca2+ load remained normal. beta-Adrenergic stimulation enhanced pacemaking of both genotypes, though, Ca(v)1.3(-/-) SAN cells remained slower than WT. Conversely, we rescued pacemaker activity in Ca(v)1.3(-/-) SAN cells and intact tissues through caffeine-mediated stimulation of Ca2+-induced Ca2+ release. Ca(v)1.3 channels play a critical role in the regulation of [Ca2+](i) dynamics, providing an unanticipated mechanism for triggering local [Ca2+](i) releases and thereby controlling pacemaker activity. Our study also provides an additional pathophysiological mechanism for congenital SAN dysfunction and heart block linked to Ca(v)1.3 loss of function in humans.
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