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Bondarenko, AI; Panasiuk, O; Okhai, I; Montecucco, F; Brandt, KJ; Mach, F.
Direct activation of Ca²⁺ and voltage-gated potassium channels of large conductance by anandamide in endothelial cells does not support the presence of endothelial atypical cannabinoid receptor.
Eur J Pharmacol. 2017; 805(5):14-24 Doi: 10.1016/j.ejphar.2017.03.038 [OPEN ACCESS]
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Leading authors Med Uni Graz: Bondarenko Oleksandr
Co-authors Med Uni Graz: Panasiuk Olga
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Abstract:: Endocannabinoid anandamide induces endothelium-dependent relaxation commonly attributed to stimulation of the G-protein coupled endothelial anandamide receptor. The study addressed the receptor-independent effect of anandamide on large conductance Ca²⁺-dependent K⁺ channels expressed in endothelial cell line EA.hy926. Under resting conditions, 10µM anandamide did not significantly influence the resting membrane potential. In a Ca²⁺-free solution the cells were depolarized by ~10mV. Further administration of 10µM anandamide hyperpolarized the cells by ~8mV. In voltage-clamp mode, anandamide elicited the outwardly rectifying whole-cell current sensitive to paxilline but insensitive to GDPβS, a G-protein inhibitor. Administration of 70µM Mn²⁺, an agent used to promote integrin clustering, reversibly stimulated whole-cell current, but failed to further facilitate the anandamide-stimulated current. In an inside-out configuration, anandamide (0.1-30µM) facilitated single BK_Ca channel activity in a concentration-dependent manner within a physiological Ca²⁺ range and a wide range of voltages, mainly by reducing mean closed time. The effect is essentially eliminated following chelation of Ca²⁺ from the cytosolic face and pre-exposure to cholesterol-reducing agent methyl-β-cyclodextrin. O-1918 (3µM), a cannabidiol analog used as a selective antagonist of endothelial anandamide receptor, reduced BK_Ca channel activity in inside-out patches. These results do not support the existence of endothelial cannabinoid receptor and indicate that anandamide acts as a direct BK_Ca opener. The action does not require cell integrity or integrins and is caused by direct modification of BK_Ca channel activity. Copyright © 2017 Elsevier B.V. All rights reserved.
Find related publications in this database (using NLM MeSH Indexing): Arachidonic Acids - pharmacology; Calcium - metabolism; Cell Membrane - drug effects; Cell Membrane - metabolism; Cholesterol - metabolism; Endocannabinoids - pharmacology; Human Umbilical Vein Endothelial Cells - cytology; Human Umbilical Vein Endothelial Cells - drug effects; Human Umbilical Vein Endothelial Cells - metabolism; Humans -; Ion Channel Gating - drug effects; Large-Conductance Calcium-Activated Potassium Channels - metabolism; Polyunsaturated Alkamides - pharmacology; Potassium Channels, Voltage-Gated - metabolism; Receptors, Cannabinoid - metabolism
Find related publications in this database (Keywords): Anandamide; Endothelial cannabinoid receptor; Integrins; BKCa channels