G Protein-coupled Endothelial Receptor for Atypical Cannabinoid Ligands Modulates a Ca2+-dependent K+ Current

Abstract

The cannabinoid analog "abnormal cannabidiol" (abn-cbd) causes endothelium-dependent vasodilation in rat isolated mesenteric arteries through a G protein-coupled receptor distinct from CB 1 or CB 2 . We examined the actions of abn-cbd on the electrophysiology of human umbilical vein endothelial cells (HU-VEC), using the whole cell version of the patch clamp technique. Voltage steps produced noninactivating outward currents, which were abolished by iberiotoxin or by chelation of intracellular calcium. The presence of a BK Ca channel in HUVEC was documented by reverse transcriptase-PCR. Abn-cbd concentration dependently potentiated the outward current produced by a single voltage step. This potentiation was abolished by the cannabidiol analog O-1918 or by pertussis toxin but was unaffected by CB 1 or CB 2 antagonists. HU-210, a CB 1 /CB 2 receptor agonist, had no effect on the outward current. Clamping The marijuana plant contains more than 60 chemical substances of which ⌬ 9 -tetrahydrocannabinol is the main psychoactive ingredient (1).

Cannabinoids and neuroinflammation

“…Two cannabinoid G protein-coupled receptors have been cloned thus far, CB 1 receptors (Matsuda et al, 1990), expressed primarily by neurons, and CB 2 receptors (Munro et al, 1993), expressed primarily by immune cells. Aside from these two receptors, evidence exists supporting the presence of yet uncloned cannabinoid receptors, a hypothesis predominantly based on pharmacological activity of cannabinoid compounds in CB 1 and CB 2 receptor-deficient mice or following the administration of 'selective' CB 1 and CB 2 receptor antagonists (Jarai et al, 1999;Di Marzo et al, 2000;Breivogel et al, 2001;Hajos & Freund, 2002;Begg et al, 2003). Here cannabinoids are defined as ingredients of the cannabis plant or other compounds that bind to and activate cannabinoid receptors, and Table 1 summarizes their pharmacological properties.…”

Cannabinoid Receptors and Endocannabinoids: Evidence for New Players

“…99 Several lines of evidence suggest that endothelial cells express this novel cannabinoid receptor, and its activation leads to the release of nitric oxide, culminating in the opening of potassium channels on vascular smooth muscle and leading to relaxation and vasodilation. 100 Although there are strong pharmacological parallels between the vascular and hippocampal novel receptors, there are some notable differences. For example, the vascular receptor is insensitive to potent synthetic cannabinoids.…”

Prospects for Creation of Cardioprotective Drugs Based on Cannabinoid Receptor Agonists

“…This receptor exhibited a high affinity to the regioisomer of cannabidiol, abnormal cannabidiol. 19,20 This receptor promoted endothelium-dependent vasodilation of isolated rat mesenteric arteries via opening of Ca 2+ -dependent K + channel. 19,20 19 It has been also established that in endothelial cells abnormal cannabidiol activates extracellular signal-regulated kinase (ERK) and Akt kinase.…”

“…19,20 This receptor promoted endothelium-dependent vasodilation of isolated rat mesenteric arteries via opening of Ca 2+ -dependent K + channel. 19,20 19 It has been also established that in endothelial cells abnormal cannabidiol activates extracellular signal-regulated kinase (ERK) and Akt kinase. 20 Abnormal cannabidiol-induced vasorelaxation was maintained after inhibition of NO-synthase by L-NAME or in combination with vanilloid VR1 receptor antagonist capsazepine.…”