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Biochem Pharmacol. 2012 Oct 15;84(8):1024-35. doi: 10.1016/j.bcp.2012.07.013. Epub 2012 Jul 26.

Store-independent pathways for cytosolic STIM1 clustering in the regulation of store-operated Ca(2+) influx.

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Centre for Cardiovascular and Metabolic Research, Hull York Medical School, University of Hull, Hull, HU6 7RX, UK.


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.

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