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The endocannabinoid N-arachidonoyl glycine (NAGly) inhibits store-operated Ca2+ entry by preventing STIM1-Orai1 interaction.
J Cell Sci 2013; 126(Pt 4):879-88JC

Abstract

The endocannabiniod anandamide (AEA) and its derivate N-arachidonoyl glycine (NAGly) have a broad spectrum of physiological effects, which are induced by both binding to receptors and receptor-independent modulations of ion channels and transporters. The impact of AEA and NAGly on store-operated Ca(2+) entry (SOCE), a ubiquitous Ca(2+) entry pathway regulating many cellular functions, is unknown. Here we show that NAGly, but not AEA reversibly hinders SOCE in a time- and concentration-dependent manner. The inhibitory effect of NAGly on SOCE was found in the human endothelial cell line EA.hy926, the rat pancreatic β-cell line INS-1 832/13, and the rat basophilic leukemia cell line RBL-2H3. NAGly diminished SOCE independently from the mode of Ca(2+) depletion of the endoplasmic reticulum, whereas it had no effect on Ca(2+) entry through L-type voltage-gated Ca(2+) channels. Enhanced Ca(2+) entry was effectively hampered by NAGly in cells overexpressing the key molecular constituents of SOCE, stromal interacting molecule 1 (STIM1) and the pore-forming subunit of SOCE channels, Orai1. Fluorescence microscopy revealed that NAGly did not affect STIM1 oligomerization, STIM1 clustering, or the colocalization of STIM1 with Orai1, which were induced by Ca(2+) depletion of the endoplasmic reticulum. In contrast, independently from its slow depolarizing effect on mitochondria, NAGly instantly and strongly diminished the interaction of STIM1 with Orai1, indicating that NAGly inhibits SOCE primarily by uncoupling STIM1 from Orai1. In summary, our findings revealed the STIM1-Orai1-mediated SOCE machinery as a molecular target of NAGly, which might have many implications in cell physiology.

Authors+Show Affiliations

Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University Graz, Graz, Austria.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

23239024

Citation

Deak, Andras T., et al. "The Endocannabinoid N-arachidonoyl Glycine (NAGly) Inhibits Store-operated Ca2+ Entry By Preventing STIM1-Orai1 Interaction." Journal of Cell Science, vol. 126, no. Pt 4, 2013, pp. 879-88.
Deak AT, Groschner LN, Alam MR, et al. The endocannabinoid N-arachidonoyl glycine (NAGly) inhibits store-operated Ca2+ entry by preventing STIM1-Orai1 interaction. J Cell Sci. 2013;126(Pt 4):879-88.
Deak, A. T., Groschner, L. N., Alam, M. R., Seles, E., Bondarenko, A. I., Graier, W. F., & Malli, R. (2013). The endocannabinoid N-arachidonoyl glycine (NAGly) inhibits store-operated Ca2+ entry by preventing STIM1-Orai1 interaction. Journal of Cell Science, 126(Pt 4), pp. 879-88. doi:10.1242/jcs.118075.
Deak AT, et al. The Endocannabinoid N-arachidonoyl Glycine (NAGly) Inhibits Store-operated Ca2+ Entry By Preventing STIM1-Orai1 Interaction. J Cell Sci. 2013 Feb 15;126(Pt 4):879-88. PubMed PMID: 23239024.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The endocannabinoid N-arachidonoyl glycine (NAGly) inhibits store-operated Ca2+ entry by preventing STIM1-Orai1 interaction. AU - Deak,Andras T, AU - Groschner,Lukas N, AU - Alam,Muhammad Rizwan, AU - Seles,Elisabeth, AU - Bondarenko,Alexander I, AU - Graier,Wolfgang F, AU - Malli,Roland, Y1 - 2012/12/13/ PY - 2012/12/15/entrez PY - 2012/12/15/pubmed PY - 2013/11/20/medline SP - 879 EP - 88 JF - Journal of cell science JO - J. Cell. Sci. VL - 126 IS - Pt 4 N2 - The endocannabiniod anandamide (AEA) and its derivate N-arachidonoyl glycine (NAGly) have a broad spectrum of physiological effects, which are induced by both binding to receptors and receptor-independent modulations of ion channels and transporters. The impact of AEA and NAGly on store-operated Ca(2+) entry (SOCE), a ubiquitous Ca(2+) entry pathway regulating many cellular functions, is unknown. Here we show that NAGly, but not AEA reversibly hinders SOCE in a time- and concentration-dependent manner. The inhibitory effect of NAGly on SOCE was found in the human endothelial cell line EA.hy926, the rat pancreatic β-cell line INS-1 832/13, and the rat basophilic leukemia cell line RBL-2H3. NAGly diminished SOCE independently from the mode of Ca(2+) depletion of the endoplasmic reticulum, whereas it had no effect on Ca(2+) entry through L-type voltage-gated Ca(2+) channels. Enhanced Ca(2+) entry was effectively hampered by NAGly in cells overexpressing the key molecular constituents of SOCE, stromal interacting molecule 1 (STIM1) and the pore-forming subunit of SOCE channels, Orai1. Fluorescence microscopy revealed that NAGly did not affect STIM1 oligomerization, STIM1 clustering, or the colocalization of STIM1 with Orai1, which were induced by Ca(2+) depletion of the endoplasmic reticulum. In contrast, independently from its slow depolarizing effect on mitochondria, NAGly instantly and strongly diminished the interaction of STIM1 with Orai1, indicating that NAGly inhibits SOCE primarily by uncoupling STIM1 from Orai1. In summary, our findings revealed the STIM1-Orai1-mediated SOCE machinery as a molecular target of NAGly, which might have many implications in cell physiology. SN - 1477-9137 UR - https://www.unboundmedicine.com/medline/citation/23239024/The_endocannabinoid_N_arachidonoyl_glycine__NAGly__inhibits_store_operated_Ca2+_entry_by_preventing_STIM1_Orai1_interaction_ L2 - http://jcs.biologists.org/cgi/pmidlookup?view=long&pmid=23239024 DB - PRIME DP - Unbound Medicine ER -