Cardiac excitation-contraction coupling: Role of membrane potential in regulation of contraction

The steps that couple depolarization of the cardiac cell membrane to initiation of contraction remain controversial. Depolarization triggers a rise in intracellular free Ca²⁺ which activates contractile myofilaments. Most of this Ca²⁺ is released from the sarcoplasmic reticulum (SR). Two fundamentally different mechanisms have been proposed for SR Ca²⁺ release: Ca²+ -induced Ca²⁺ release (CICR) and a voltage-sensitive release mechanism (VSRM). Both mechanisms operate in the same cell and may contribute to contraction. CICR couples the release of SR Ca²⁺ closely to the magnitude of the L-type Ca²⁺ current. In contrast, the VSRM is graded by membrane potential rather than Ca²⁺ current. The electrophysiological and pharmacological characteristics of the VSRM are strikingly different from CICR. Furthermore, the VSRM is strongly modulated by phosphorylation and provides a new regulatory mechanism for cardiac contraction. The VSRM is depressed in heart failure and may play an important role in contractile dysfunction. This review explores the operation and characteristics of the VSRM and CICR and discusses the impact of the VSRM on our understanding of cardiac excitation-contraction coupling.