Conformational activation of Ca ²⁺ entry by depolarization of skeletal myotubes

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.