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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

Shang Zhong Xu


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.

Journal Article Type Article
Publication Date Oct 15, 2012
Journal Biochemical Pharmacology
Print ISSN 0006-2952
Electronic ISSN 1873-2968
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 84
Issue 8
Pages 1024-1035
APA6 Citation 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). doi:10.1016/j.bcp.2012.07.013. ISSN 1873-2968
Keywords STIM1; 2-Aminoethoxydiphenyl borate; Store-operated Ca2+ channels; Mitochondrial Ca2+ release; ORAI
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