STIM1 has a plasma membrane role in the activation of store-operated Ca2+ channels

Maria A. Spassova, Jonathan Soboloff, Li Ping He, Wen Xu, Marie A. Dziadek, Donald L. Gill

Research output: Contribution to journalArticlepeer-review

263 Scopus citations

Abstract

Receptor-induced Ca2+ signals are key to the function of all cells and involve release of Ca2+ from endoplasmic reticulum (ER) stores, triggering Ca2+ entry through plasma membrane (PM) "store-operated channels" (SOCs). The identity of SOCs and their coupling to store depletion remain molecular and mechanistic mysteries. The single transmembrane-spanning Ca2+-binding protein, STIM1, is necessary in this coupling process and is proposed to function as an ER Ca 2+ sensor to provide the trigger for SOC activation. Here we reveal that, in addition to being an ER Ca2+ sensor, STIM1 functions within the PM to control operation of the Ca2+ entry channel itself. Increased expression levels of STIM1 correlate with a gain in function of Ca2+ release-activated Ca2+ (CRAC) channel activity. Point mutation of the N-terminal EF hand transforms the CRAC channel current (I CRAC) into a constitutively active, Ca2+ store-independent mode. Mutants in the EF hand and cytoplasmic C terminus of STIM1 alter operational parameters of CRAC channels, including pharmacological profile and inactivation properties. Last, Ab externally applied to the STIM1 N-terminal EF hand blocks both ICRAC in hematopoietic cells and SOC-mediated Ca2+ entry in HEK293 cells, revealing that STIM1 has an important functional presence within the PM. The results reveal that, in addition to being an ER Ca2+ sensor, STIM1 functions within the PM to exert control over the operation of SOCs. As a cell surface signaling protein, STIM1 represents a key pharmacological target to control fundamental Ca 2+-regulated processes including secretion, contraction, metabolism, cell division, and apoptosis.

Original languageEnglish (US)
Pages (from-to)4040-4045
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number11
DOIs
StatePublished - Mar 14 2006

All Science Journal Classification (ASJC) codes

  • General

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