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Store-independent pathways for cytosolic STIM1 clustering in the regulation of store-operated Ca2+ influx

Zeng, Bo; Chen, Gui-Lan; Xu, Shang Zhong


Bo Zeng

Gui-Lan Chen


STIM1 is a Ca 2+ sensing molecule. Once the Ca 2+ stores are depleted, STIM1 moves towards the plasma membrane (PM) (translocation), forms puncta (clustering), and triggers store-operated Ca 2+ entry (SOCE). Although this process has been regarded as a main mechanism for store-operated Ca 2+ channel activation, the STIM1 clustering is still unclear. Here we discovered a new phenomenon of STIM1 clustering, which is not triggered by endoplasmic reticulum (ER) Ca 2+ depletion. STIM1 subplasmalemmal translocation and clustering can be induced by ER Ca 2+ store depletion with thapsigargin (TG), G-protein-coupled receptor activator trypsin and ryanodine receptor (RyR) agonists caffeine and 4-chloro-3-ethylphenol (4-CEP) in the HEK293 cells stably transfected with STIM1-EYFP. The STIM1 clustering induced by TG was more sustained than that induced by trypsin and RyR agonists. Interestingly, 4-CEP-induced STIM1 clustering also happened in the cytosol without ER Ca 2+ store depletion. Application of some pharmacological regulators including flufenamic acid, 2-APB, and carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP) at concentrations without affecting ER Ca 2+ store also evoked cytosolic STIM1 clustering. However, the direct store-operated ORAI channel blockers (SKF-96365, Gd 3+ and diethylstilbestrol) or the signaling pathway inhibitors (genistein, wortmannin, Y-27632, forskolin and GF109203X) did not change the STIM1 movement. Disruption of cytoskeleton by colchicine and cytochalasin D also showed no effect on STIM1 movement. We concluded that STIM1 clustering and translocation are two dynamic processes that can be pharmacologically dissociated. The ER Ca 2+ store-independent mechanism for STIM1 clustering is a new alternative mechanism for regulating store-operated channel activity, which could act as a new pharmacological target. © 2012 Elsevier Inc.


Zeng, B., Chen, G., & Xu, S. Z. (2012). Store-independent pathways for cytosolic STIM1 clustering in the regulation of store-operated Ca2+ influx. Biochemical Pharmacology, 84(8), 1024-1035.

Journal Article Type Article
Acceptance Date Jul 16, 2012
Online Publication Date Jul 26, 2012
Publication Date Oct 15, 2012
Deposit Date Nov 13, 2014
Journal Biochemical Pharmacology
Print ISSN 0006-2952
Electronic ISSN 1873-2968
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 84
Issue 8
Pages 1024-1035
Keywords STIM1; 2-Aminoethoxydiphenyl borate; Store-operated Ca2+ channels; Mitochondrial Ca2+ release; ORAI
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