In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 103, No. 11 ( 2006-03-14), p. 4040-4045
Abstract:
Receptor-induced Ca 2+ signals are key to the function of all cells and involve release of Ca 2+ from endoplasmic reticulum (ER) stores, triggering Ca 2+ 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 Ca 2+ -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 Ca 2+ sensor, STIM1 functions within the PM to control operation of the Ca 2+ entry channel itself. Increased expression levels of STIM1 correlate with a gain in function of Ca 2+ release-activated Ca 2+ (CRAC) channel activity. Point mutation of the N-terminal EF hand transforms the CRAC channel current ( I CRAC ) into a constitutively active, Ca 2+ 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 I CRAC in hematopoietic cells and SOC-mediated Ca 2+ 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 Ca 2+ 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.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.0510050103
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2006
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
