Alternative splicing converts STIM2 from an activator to an inhibitor of store-operated calcium channels.

ABSTRACT: Store-operated calcium entry (SOCE) regulates a wide variety of essential cellular functions. SOCE is mediated by STIM1 and STIM2, which sense depletion of ER Ca(2+) stores and activate Orai channels in the plasma membrane. Although the amplitude and dynamics of SOCE are considered important determinants of Ca(2+)-dependent responses, the underlying modulatory mechanisms are unclear. In this paper, we identify STIM2?, a highly conserved alternatively spliced isoform of STIM2, which, in contrast to all known STIM isoforms, is a potent inhibitor of SOCE. Although STIM2? does not by itself strongly bind Orai1, it is recruited to Orai1 channels by forming heterodimers with other STIM isoforms. Analysis of STIM2? mutants and Orai1-STIM2? chimeras suggested that it actively inhibits SOCE through a sequence-specific allosteric interaction with Orai1. Our results reveal a previously unrecognized functional flexibility in the STIM protein family by which alternative splicing creates negative and positive regulators of SOCE to shape the amplitude and dynamics of Ca(2+) signals.

SUBMITTER: Rana A 

PROVIDER: S-EPMC4460148 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature