Ca2+ -induced Ca2+ release at the terminal cisternae of skeletal sarcoplasmic reticulum was demonstrated using heavy sarcoplasmic reticulum vesicles. Ca2+ release was observed at 10 mum Ca2+ in the presence of 1.25 mm free Mg2+ and was sensitive to low concentrations of ruthenium red and was partially inhibited by valinomycin. These results suggest that the Ca2+ -induced Ca2+ release is electrogenic and that an inside negative membrane potential created by the Ca2+ flux opens a second channel that releases Ca2+. Results in support of this formulation were obtained by applying a Cl- gradient or K+ gradient to sarcoplasmic reticulum vesicles to initiate Ca2+ release. Based on experiments the following hypothesis for the excitation-contraction coupling of skeletal muscle was formulated. On excitation, small amounts of Ca2+ enter from the transverse tubule and interact with a Ca2+ enter from the transverse tubule and interact with a Ca2+ receptor at the terminal cisternae and cause Ca2+ release (Ca2+ -induced Ca2+ release). This Ca2+ flux generates an inside negative membrane potential which opens voltage-gated Ca2+ channels (membrane potential-dependent Ca2+ release) in amounts sufficient for contraction.