The quest for endothelial atypical cannabinoid receptor: BKCa channels act as cellular sensors for cannabinoids in in vitro and in situ endothelial cells

• Published in: Vascular pharmacology Vol. 102; pp. 44 - 55
• Main Authors: Bondarenko, Alexander I., Panasiuk, Olga, Drachuk, Konstantin, Montecucco, Fabrizio, Brandt, Karim J., Mach, François
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01-03-2018
• Subjects: Abnormal cannabidiol; BKCa channels; Endothelial cells; Mouse aorta; N-arachidonoyl glycine; Rimonabant; BKCa channels; Rimonabant; Abnormal cannabidiol; Mouse aorta; N-arachidonoyl glycine; Endothelial cells
• ISSN: 1537-1891; 1879-3649
• DOI: 10.1016/j.vph.2018.01.004

Endothelium-dependent component of cannabinoid-induced vasodilation has been postulated to require G-protein-coupled non-CB1/CB2 endothelial cannabinoid (eCB) receptor. GPR18 was proposed as a candidate for eCBR. To address the hypothesis that the effects attributed to eCBR are mediated by G-protein-coupled receptor (GPCR)-independent targets, we studied the electrical responses in endothelial cells, focusing on BKCa channels. In patches excised from endothelial-derived EA.hy926 cells, N-arachidonoyl glycine (NAGly) and abnormal cannabidiol (abn-cbd), prototypical agonists for eCB receptor, stimulate single BKCa activity in a concentration- and Ca2+-dependent manner. The postulated eCB receptor inhibitors rimonabant and AM251 were found to inhibit basal and stimulated by NAGly- and abn-cbd BKCa activity in cell-free patches. In isolated mice aortas, abn-cbd and NAGly produced endothelial cell hyperpolarization that was sensitive to paxilline, a selective BKCa inhibitor, but not to GPR18 antibody, and mimicked by NS1619, a direct BKCa opener. In excised patches from mice aortic endothelium, single channel activity with characteristics similar to BKCa was established by the addition of abn-cbd and NAGly. We conclude that the two cannabinoids abn-cbd and NAGly initiate a GPR18-independent activation of BKCa channels in mice aortic endothelial cells that might contribute to vasodilation to cannabinoids.
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