Modulation of Ca2+ channel-gated Ca2+ release by W-7 in cardiac myocytes

Abstract

Cardiac muscle excitation-contraction coupling is controlled by the Ca2+-induced Ca2+ release mechanism. The present study examines the effects of a calmodulin antagonist W-7 on Ca2+ current (I(Ca))-induced Ca2+ release in whole cell-clamped rat ventricular myocytes. Exposure of cells to W-7 suppressed I(Ca), but the intracellular Ca2+ transients showed a lesser degree of reduction, suggesting possible enhancement of Ca2+-induced Ca2+ release. The effects of W-7 on the efficacy of Ca2+ release were most prominent at negative potentials. At test potentials of -30 mV, 20 μM W-7 almost completely blocked I(Ca), but significant Ca2+-transients remained, thus causing a four to six-fold increase in the efficacy of Ca2+-induced Ca2+ release. The depolarization-dependent Ca2+-transients were eliminated in absence of extracellular Ca2+, blocked by Cd2+, and were absent when the sarcoplasmic reticulum was depleted of Ca2+, implicating dependency on Ca2+-signaling between the L-type channel and the ryanodine receptor. W-7 mediated increase in the efficacy of Ca2+-induced Ca2+ release was eliminated when myocytes were dialyzed with the internal solution containing gluathione (5 mM), suggesting the possible role of cellular redox state in the regulation of Ca2+ release by the calmodulin antagonist.