The 1996 Merck Frost Award. The voltage-sensitive release mechanism: A new trigger for cardiac contraction

Contraction in mammalian heart is initiated by a rapid rise in intracellular free calcium (Ca²⁺) triggered by excitation of the sarcolemma. Traditional views of cardiac excitation-contraction coupling have focused on the importance of Ca²⁺-induced Ca²⁺ release from the sarcoplasmic reticulum as a major source for this increase in Ca²⁺. Influx of Ca²⁺, primarily through L-type Ca²⁺ channels and the sodium-calcium (Na⁺-Ca²⁺) exchanger, is considered to be the main trigger for Ca²⁺-induced Ca²⁺ release. However, we recently have discovered a new trigger for excitation-contraction coupling in experiments on isolated ventricular myocytes under voltage clamp conditions. This trigger is a voltage-sensitive release mechanism that initiates release of Ca²⁺ from the sarcoplasmic reticulum. This article reviews the development of the concept of voltage-activated Ca²⁺ release in heart and discusses the importance of this discovery to the physiology, pathophysiology, and pharmacology of cardiac contraction.