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Significance Ca2+ entry mediated by the plasma membrane (PM) channel Orai1 controls nuclear factor of activated T cells 1 (NFAT1)-dependent gene expression that regulates critical cellular functions. Ca2+ -sensing endoplasmic reticulum (ER) proteins, STIM1 and STIM2, regulate Orai1 function in response to decreases in [Ca2+ ]ER . While STIM1 is the primary regulator of Orai1 activity, STIM2 has a minor contribution to Ca2+ entry but is relevant for Ca2+ -dependent NFAT1 activation. Here we report that STIM2 recruits Orai1/STIM1 to ER-PM junctions and promotes channel assembly with the AKAP79 signaling complex. The latter is an important step that allows Ca2+ entry mediated by Orai1 to be specifically used for NFAT1 activation. Our findings reveal that STIM2 enhances the coupling of Orai1 function with NFAT1 activation.

STIM2 targets Orai1/STIM1 to the AKAP79 signaling complex and confers coupling of Ca 2+ entry with NFAT1 activation

STIM2 targets Orai1/STIM1 to the AKAP79 signaling complex and confers coupling of Ca ²⁺ entry with NFAT1 activation