Store-operated Ca 2+ entry (SOCE) occurs in diverse cell types in response to depletion of Ca 2+ within the endoplasmic/sarcoplasmic reticulum and functions both to refill these stores and to shape cytoplasmic Ca 2+ transients. Here we report that in addition to conventional SOCE, skeletal myotubes display a physiological mechanism that we term excitation-coupled Ca 2+ entry (ECCE). ECCE is rapidly initiated by membrane depolarization. Like excitation-contraction coupling, ECCE is absent in both dyspedic myotubes that lack the skeletal muscle-type ryanodine receptor 1 and dysgenic myotubes that lack the dihydropyridine receptor (DHPR), and is independent of the DHPR l -type Ca 2+ current. Unlike classic SOCE, ECCE does not depend on sarcoplasmic reticulum Ca 2+ release. Indeed, ECCE produces a large Ca 2+ entry in response to physiological stimuli that do not produce substantial store depletion and depends on interactions among three different Ca 2+ channels: the DHPR, ryanodine receptor 1, and a Ca 2+ entry channel with properties corresponding to those of store-operated Ca 2+ channels. ECCE may provide a fundamental means to rapidly maintain Ca 2+ stores and control important aspects of Ca 2+ signaling in both muscle and nonmuscle cells.

Bi-directional signaling between ryanodine receptor type 1 (RyR1) and dihydropyridine receptor (DHPR) in skeletal muscle serves as a prominent example of conformational coupling. Evidence for a physiological mechanism that upon depolarization of myotubes tightly couples three calcium channels, DHPR, RyR1, and