Endothelial atypical cannabinoid receptor: do we have enough evidence?

Abstract

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-CB1, non-CB2 Gi/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 Gi/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 implications 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 Gi/o protein-dependent endothelial cannabinoid signalling from that involving the classical CB1 and CB2 receptors as well as its relevance for pathophysiological conditions. AbbreviationsAbn-CBD, abnormal cannabidiol; ARA-S, N-arachidonyl serine; BKCa, high-conductance Ca 2+ -dependent K

Intracellular Ca2+ release decelerates mitochondrial cristae dynamics within the junctions to the endoplasmic reticulum

“…Ionomycin (200 nM) was used to evoke global Ca 2+ release from the ER [2, 3]. Cells were imaged with and without the addition of ionomycin.…”

Big conductance calcium‐activated potassium channel openers control spasticity without sedation

“…These compounds and O‐1918 antagonize the action of VSN16R in mesenteric artery relaxation assays (Hoi et al, ), and these effects were used to help identify the target for VSN16R activity. It has been reported that O‐1918 can target GPR18 and GPR55, candidates for a putative non‐CB 1 /CB 2 vascular cannabinoid receptor that is activated by some endocannabinoids (Baker et al, ; McHugh et al, ; Bondarenko, ). Stimulation of this vascular target has been associated with the development of low blood pressure in some studies (Bondarenko, ); however, it was clear that VSN16R did not induce hypotension in rodents (Hoi et al, ), dogs and humans (Supporting Information Tables 5S and S9).…”

“…It has been reported that O‐1918 can target GPR18 and GPR55, candidates for a putative non‐CB 1 /CB 2 vascular cannabinoid receptor that is activated by some endocannabinoids (Baker et al, ; McHugh et al, ; Bondarenko, ). Stimulation of this vascular target has been associated with the development of low blood pressure in some studies (Bondarenko, ); however, it was clear that VSN16R did not induce hypotension in rodents (Hoi et al, ), dogs and humans (Supporting Information Tables 5S and S9). GPR18 and notably GPR55 are bound by SR141716A and AM251 (Baker et al, ; Pertwee et al, ).…”

“…Likewise, N‐arachidonoyl serine that may act on GPR55 can inhibit vasorelaxation by endothelial cell‐dependent and independent mechanisms following direct BK Ca activity that was directly blocked by O‐1918 (Godlewski et al, ). This suggested that BK Ca channels may mediate the vasorelaxing effects of at least some cannabinoids (Bondarenko, ). VSN16R had no effects on the primary porcine aorta endothelium (Supporting Information Figure S4), but in assays in third‐order rat mesenteric arteries, VSN16R induce significant vasorelaxation in an endothelium‐dependent manner (Figure C) and this effect was significantly inhibited by antagonists of BK Ca channels, notably by iberotoxin and charybdotoxin.…”

“…As such, both gain and loss of function of the BK Ca channels can lead to neural hyperexcitability (N'Gouemo, ). The BK Ca channels also appear to be part of the signalling machinery of some cannabinoid‐related GPCRs, such as GPR55 (Bondarenko et al, ; Bondarenko, ) and potentially the CB 1 receptor (Sánchez‐Pastor et al, ). In addition, being calcium‐dependent, BK Ca channel activity and VSN16R function may also be modulated secondary to alterations to intracellular calcium stimulation, or other intracellular signalling molecules, following activity of other receptors.…”