STIM1 carboxyl-terminus activates native SOC, Icrac and TRPC1 channels

Guo N. Huang, Weizhong Zeng, Joo Young Kim, Joseph P. Yuan, Linhuang Han, Shmuel Muallem, Paul F. Worley

Research output: Contribution to journalArticlepeer-review

538 Scopus citations


Receptor-evoked Ca2+ signalling involves Ca2+ release from the endoplasmic reticulum, followed by Ca2+ influx across the plasma membrane1. Ca2+ influx is essential for many cellular functions, from secretion to transcription, and is mediated by Ca2+-release activated Ca2+ (Icrac) channels and store-operated calcium entry (SOC) channels. Although the molecular identity and regulation of Icrac and SOC channels have not been precisely determined, notable recent findings are the identification of STIM1, which has been indicated to regulate SOC and Icrac channels by functioning as an endoplasmic reticulum Ca2+ sensor3-6), and ORAI1 (ref. 7) or CRACM1 (ref. 8) - both of which may function as Icrac channels or as an Icrac subunit. How STIM1 activates the Ca2+ influx channels and whether STIM1 contributes to the channel pore remains unknown. Here, we identify the structural features that are essential for STIM1-dependent activation of SOC and Icrac channels, and demonstrate that they are identical to those involved in the binding and activation of TRPC1. Notably, the cytosolic carboxyl terminus of STIM1 is sufficient to activate SOC, Icrac and TRPC1 channels even when native STIM1 is depleted by small interfering RNA. Activity of STIM1 requires an ERM domain, which mediates the selective binding of STIM1 to TRPC1, 2 and 4, but not to TRPC3, 6 or 7, and a cationic lysine-rich region, which is essential for gating of TRPC1. Deletion of either region in the constitutively active STIM1D76A yields dominant-negative mutants that block native SOC channels, expressed TRPC1 in HEK293 cells and Icrac in Jurkat cells. These observations implicate STIM1 as a key regulator of activity rather than a channel component, and reveal similar regulation of SOC, Icrac and TRPC channel activation by STIM1.

Original languageEnglish (US)
Pages (from-to)1003-1010
Number of pages8
JournalNature cell biology
Issue number9
StatePublished - Sep 2006

ASJC Scopus subject areas

  • Cell Biology


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