Conformational activation of Ca2+ entry by depolarization of skeletal myotubes

Store-operated Ca2+ entry (SOCE) occurs in diverse cell types in response to depletion of Ca2+ within the endoplasmic/sarcoplasmic reticulum and functions both to refill these stores and to shape cytoplasmic Ca2+ transients. Here we report that in addition to conventional SOCE, skeletal myotubes display a physiological mechanism that We term excitation-coupled Ca2+ 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 Ca2+ current. Unlike classic SOCE, ECCE does, not depend on sarcoplasmic reticulum Ca2+ release. Indeed, ECCE produces a large Ca2+ entry in response to physiological stimuli that do not produce substantial store depletion and depends on interactions among three different Ca2+ channels: the DHPR, ryanodine receptor 1, and a Ca2+ entry channel with properties corresponding to those of store-operated Ca2+ channels. ECCE may provide a fundamental means to rapidly maintain Ca2+ stores and control important aspects of Ca2+ Signaling in both muscle and nonmuscle cells.