Molecular mechanism for the regulation of Ca²⁺ signaling and its failure in the heart.

Abstract

In cardiac excitation-contraction (E-C) coupling, the cross-signaling between L-type Ca²⁺ channels and ryanodine receptors (RyRs) is the initial regulatory step of Ca²⁺ signaling. Small Ca²⁺ influx through L-type Ca²⁺ channels is amplified via Ca²⁺-induced Ca²⁺ release (CICR) from nearby RyRs, where the Ca²⁺-dependent inactivation of cardiac L-type Ca²⁺ channels plays a critical role in the fine-tuning of CICR and thus the SR Ca²⁺ content. The bimodal regulation of subsarcolemmal Ca²⁺ concentration via Na⁺-Ca²⁺ exchanger is also involved in the positive and negative control of CICR. The impairment of the fine-tuning mechanism of CICR evokes the compensatory mechanisms and triggers the pathological Ca²⁺ signaling, which lead to hypertrophy and electrophysiological remodeling in cardiac myocytes. The molecular mechanism underlying physiological regulation and deterioration of the fine-tuning of CICR and Ca²⁺ signaling will be further discussed. [Jpn J Physiol 55 Suppl:S55 (2005)]