The calcium store sensor, STIM1, reciprocally controls Orai and Ca _V1.2 channels

Calcium signals, pivotal in controlling cell function, can be generated by calcium entry channels activated by plasma membrane depolarization or depletion of internal calcium stores. We reveal a regulatory link between these two channel subtypes mediated by the ubiquitous calcium-sensing STIM proteins. STIM1 activation by store depletion or mutational modification strongly suppresses voltage-operated calcium (Ca_V1.2) channels while activating store-operated Orai channels. Both actions are mediated by the short STIM-Orai activating region (SOAR) of STIM1. STIM1 interacts with Ca_V1.2 channels and localizes within discrete endoplasmic reticulum/plasma membrane junctions containing both Ca_V1.2 and Orai1 channels. Hence, STIM1 interacts with and reciprocally controls two major calcium channels hitherto thought to operate independently. Such coordinated control of the widely expressed Ca_V1.2 and Orai channels has major implications for Ca ²⁺ signal generation in excitable and nonexcitable cells.