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Store-independent pathways for cytosolic STIM1 clustering in the regulation of store-operated Ca(2+) influx.
Biochem Pharmacol. 2012 Oct 15; 84(8):1024-35.BP

Abstract

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.

Authors+Show Affiliations

Centre for Cardiovascular and Metabolic Research, Hull York Medical School, University of Hull, Hull, HU6 7RX, UK.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22842488

Citation

Zeng, Bo, et al. "Store-independent Pathways for Cytosolic STIM1 Clustering in the Regulation of Store-operated Ca(2+) Influx." Biochemical Pharmacology, vol. 84, no. 8, 2012, pp. 1024-35.
Zeng B, Chen GL, Xu SZ. Store-independent pathways for cytosolic STIM1 clustering in the regulation of store-operated Ca(2+) influx. Biochem Pharmacol. 2012;84(8):1024-35.
Zeng, B., Chen, G. L., & Xu, S. Z. (2012). Store-independent pathways for cytosolic STIM1 clustering in the regulation of store-operated Ca(2+) influx. Biochemical Pharmacology, 84(8), 1024-35. https://doi.org/10.1016/j.bcp.2012.07.013
Zeng B, Chen GL, Xu SZ. Store-independent Pathways for Cytosolic STIM1 Clustering in the Regulation of Store-operated Ca(2+) Influx. Biochem Pharmacol. 2012 Oct 15;84(8):1024-35. PubMed PMID: 22842488.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Store-independent pathways for cytosolic STIM1 clustering in the regulation of store-operated Ca(2+) influx. AU - Zeng,Bo, AU - Chen,Gui-Lan, AU - Xu,Shang-Zhong, Y1 - 2012/07/26/ PY - 2012/05/30/received PY - 2012/07/08/revised PY - 2012/07/16/accepted PY - 2012/7/31/entrez PY - 2012/7/31/pubmed PY - 2012/12/14/medline SP - 1024 EP - 35 JF - Biochemical pharmacology JO - Biochem Pharmacol VL - 84 IS - 8 N2 - 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. SN - 1873-2968 UR - https://www.unboundmedicine.com/medline/citation/22842488/Store_independent_pathways_for_cytosolic_STIM1_clustering_in_the_regulation_of_store_operated_Ca_2+__influx_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-2952(12)00495-9 DB - PRIME DP - Unbound Medicine ER -