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The quest for endothelial atypical cannabinoid receptor: BKCa channels act as cellular sensors for cannabinoids in in vitro and in situ endothelial cells.
Vascul Pharmacol. 2018 03; 102:44-55.VP

Abstract

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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Authors+Show Affiliations

Bondarenko AI
Circulatory Physiology Department, Bogomoletz Institute of Physiology NAS of Ukraine, Bogomoletz Str 4, Kiev 01024, Ukraine; Institute of Molecular Biology and Biochemistry, Medical University of Graz, Harrachgasse 21/III, Graz, 8010, Austria. Electronic address: abond01@biph.kiev.ua.
Panasiuk O
Circulatory Physiology Department, Bogomoletz Institute of Physiology NAS of Ukraine, Bogomoletz Str 4, Kiev 01024, Ukraine.
Drachuk K
Circulatory Physiology Department, Bogomoletz Institute of Physiology NAS of Ukraine, Bogomoletz Str 4, Kiev 01024, Ukraine.
Montecucco F
First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 6 viale Benedetto XV, 16132 Genoa, Italy; Ospedale Policlinico San Martino, largo Benzi 10, 16132 Genoa, Italy; Centre of Excellence for Biomedical Research (CEBR), University of Genoa, 9 viale Benedetto XV, 16132 Genoa, Italy.
Brandt KJ
Division of Cardiology, Foundation for Medical Researches, Department of Internal Medicine, University of Geneva, Av. de la Roseraie 64, CH 1211, Geneva 4, Switzerland.
Mach F
Division of Cardiology, Foundation for Medical Researches, Department of Internal Medicine, University of Geneva, Av. de la Roseraie 64, CH 1211, Geneva 4, Switzerland.

MeSH

AnimalsAorta, ThoracicArachidonic AcidsCalcium Channel BlockersCannabinoid Receptor AgonistsCannabinoid Receptor AntagonistsCell LineDose-Response Relationship, DrugEndothelial CellsFemaleGlycineHuman Umbilical Vein Endothelial CellsHumansLarge-Conductance Calcium-Activated Potassium Channel alpha SubunitsMaleMembrane PotentialsMice, Inbred C57BLReceptors, CannabinoidResorcinolsSignal TransductionVasodilation

Pub Type(s)

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

Language

eng

PubMed ID

29355732

Citation

Bondarenko, Alexander I., et al. "The Quest for Endothelial Atypical Cannabinoid Receptor: BKCa Channels Act as Cellular Sensors for Cannabinoids in in Vitro and in Situ Endothelial Cells." Vascular Pharmacology, vol. 102, 2018, pp. 44-55.
Bondarenko AI, Panasiuk O, Drachuk K, et al. The quest for endothelial atypical cannabinoid receptor: BKCa channels act as cellular sensors for cannabinoids in in vitro and in situ endothelial cells. Vascul Pharmacol. 2018;102:44-55.
Bondarenko, A. I., Panasiuk, O., Drachuk, K., Montecucco, F., Brandt, K. J., & Mach, F. (2018). The quest for endothelial atypical cannabinoid receptor: BKCa channels act as cellular sensors for cannabinoids in in vitro and in situ endothelial cells. Vascular Pharmacology, 102, 44-55. https://doi.org/10.1016/j.vph.2018.01.004
Bondarenko AI, et al. The Quest for Endothelial Atypical Cannabinoid Receptor: BKCa Channels Act as Cellular Sensors for Cannabinoids in in Vitro and in Situ Endothelial Cells. Vascul Pharmacol. 2018;102:44-55. PubMed PMID: 29355732.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The quest for endothelial atypical cannabinoid receptor: BKCa channels act as cellular sensors for cannabinoids in in vitro and in situ endothelial cells. AU - Bondarenko,Alexander I, AU - Panasiuk,Olga, AU - Drachuk,Konstantin, AU - Montecucco,Fabrizio, AU - Brandt,Karim J, AU - Mach,François, Y1 - 2018/01/31/ PY - 2017/11/13/received PY - 2018/01/10/revised PY - 2018/01/16/accepted PY - 2018/1/23/pubmed PY - 2018/9/5/medline PY - 2018/1/23/entrez KW - Abnormal cannabidiol KW - BK(Ca) channels KW - Endothelial cells KW - Mouse aorta KW - N-arachidonoyl glycine KW - Rimonabant SP - 44 EP - 55 JF - Vascular pharmacology JO - Vascul Pharmacol VL - 102 N2 - 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. SN - 1879-3649 UR - https://www.unboundmedicine.com/medline/citation/29355732/The_quest_for_endothelial_atypical_cannabinoid_receptor:_BKCa_channels_act_as_cellular_sensors_for_cannabinoids_in_in_vitro_and_in_situ_endothelial_cells_ DB - PRIME DP - Unbound Medicine ER -