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The endocannabinoid N-arachidonoyl glycine (NAGly) inhibits store-operated Ca2+ entry by preventing STIM1–Orai1 interaction
Andras T. Deak, Lukas N. Groschner, Muhammad Rizwan Alam, Elisabeth Seles, Alexander I. Bondarenko, Wolfgang F. Graier, Roland Malli


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 Ca2+ entry (SOCE), a ubiquitous Ca2+ 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 Ca2+ depletion of the endoplasmic reticulum, whereas it had no effect on Ca2+ entry through L-type voltage-gated Ca2+ channels. Enhanced Ca2+ 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 Ca2+ 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.


  • Funding

    This work was supported by the Austrian Science Funds (FWF) [grant numbers P21857-B18 and P22553-B18 to W.F.G. and R.M., respectively]. A.T.D. is funded by the FWF within the PhD program Neuroscience at the Medical University of Graz. M.R.A. and E.S. are funded by the FWF within the PhD program MolMed of the Medical University of Graz. Deposited in PMC for immediate release.

  • Supplementary material available online at

  • Accepted November 16, 2012.

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