Endothelial atypical cannabinoid receptor: do we have enough evidence?

Cannabinoids and their synthetic analogues affect a broad range of physiological functions, including cardiovascular variables. Although direct evidence is still missing, the relaxation of a vast range of vascular beds induced by cannabinoids is believed to involve a still unidentified non‐ CB 1 , non‐ CB 2 G i/o protein‐coupled receptor located on endothelial cells, the so called endothelial cannabinoid receptor ( eCB receptor ) . Evidence for the presence of an eCB receptor comes mainly from vascular relaxation studies, which commonly employ pertussis toxin as an indicator for GPCR ‐mediated signalling. In addition, a pharmacological approach is widely used to attribute the relaxation to eCB receptors. Recent findings have indicated a number of GPCR ‐independent targets for both agonists and antagonists of the presumed eCB receptor , warranting further investigations and cautious interpretation of the vascular relaxation studies. This review will provide a brief historical overview on the proposed novel eCB receptor, drawing attention to the discrepancies between the studies on the pharmacological profile of the eCB receptor and highlighting the G i/o protein‐independent actions of the eCB receptor inhibitors widely used as selective compounds. As the eCB receptor represents an attractive pharmacological target for a number of cardiovascular abnormalities, defining its molecular identity and the extent of its regulation of vascular function will have important imp lications for drug discovery. This review highlights the need to re‐evaluate this subject in a thoughtful and rigorous fashion. More studies are needed to differentiate G i/o protein‐dependent endothelial cannabinoid signalling from that involving the classical CB 1 and CB 2 receptors as well as its relevance for pathophysiological conditions.