Author:
Zhang Hengtao,Sun Albert Y.,Kim Jong J.,Graham Victoria,Finch Elizabeth A.,Nepliouev Igor,Zhao Guiling,Li Tianyu,Lederer W. J.,Stiber Jonathan A.,Pitt Geoffrey S.,Bursac Nenad,Rosenberg Paul B.
Abstract
Cardiac pacemaking is governed by specialized cardiomyocytes located in the sinoatrial node (SAN). SAN cells (SANCs) integrate voltage-gated currents from channels on the membrane surface (membrane clock) with rhythmic Ca2+ release from internal Ca2+ stores (Ca2+ clock) to adjust heart rate to meet hemodynamic demand. Here, we report that stromal interaction molecule 1 (STIM1) and Orai1 channels, key components of store-operated Ca2+ entry, are selectively expressed in SANCs. Cardiac-specific deletion of STIM1 in mice resulted in depletion of sarcoplasmic reticulum (SR) Ca2+ stores of SANCs and led to SAN dysfunction, as was evident by a reduction in heart rate, sinus arrest, and an exaggerated autonomic response to cholinergic signaling. Moreover, STIM1 influenced SAN function by regulating ionic fluxes in SANCs, including activation of a store-operated Ca2+ current, a reduction in L-type Ca2+ current, and enhancing the activities of Na+/Ca2+ exchanger. In conclusion, these studies reveal that STIM1 is a multifunctional regulator of Ca2+ dynamics in SANCs that links SR Ca2+ store content with electrical events occurring in the plasma membrane, thereby contributing to automaticity of the SAN.
Funder
HHS | NIH | National Heart, Lung, and Blood Institute
Publisher
Proceedings of the National Academy of Sciences
Cited by
40 articles.
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