Abstract
Cannabinoids have been reported as orexigenic, i.e., as promoting food intake that, among others, is controlled by the so-called “hunger” hormone, ghrelin. The aim of this paper was to look for functional and/or molecular interactions between ghrelin GHSR1a and cannabinoid CB2 receptors at the central nervous system (CNS) level. In a heterologous system we identified CB2-GHSR1a receptor complexes with a particular heteromer print consisting of impairment of CB2 receptor/Gi-mediated signaling. The blockade was due to allosteric interactions within the heteromeric complex as it was reverted by antagonists of the GHSR1a receptor. Cannabinoids acting on the CB2 receptor did not affect cytosolic increases of calcium ions induced by ghrelin acting on the GHSR1a receptor. In situ proximity ligation imaging assays confirmed the expression of CB2-GHSR1a receptor complexes in both heterologous cells and primary striatal neurons. We tested heteromer expression in neurons from offspring of high-fat-diet mouse mothers as they have more risk to be obese. Interestingly, there was a marked upregulation of those complexes in striatal neurons from siblings of pregnant female mice under a high-fat diet.
Highlights
The psychotropic effects of marihuana smoking led to the discovery of cannabinoid receptors and of endocannabinoids
The CB1 receptor (CB1R), expressed mainly in neurons, is the most abundant GPCR in the nervous system; while the CB2R is expressed at lower levels both in glia and neurons located in specific regions of the brain [3,4,5,6,7]
Immunocytochemical assays in HEK293T cells transfected with the cDNA for the CB2R fused to the Green Fluorescent Protein (GFP2) and the cDNA of the GHSR1a fused to Renilla luciferase (RLuc) led to detect the receptors at the plasma membrane level with a marked colocalization (Figure 1A)
Summary
The psychotropic effects of marihuana smoking led to the discovery of cannabinoid receptors and of endocannabinoids. The characterization of cannabinoid receptors, the use of animal models of disease, and the experience of marihuana users have led to the discovery of the health-promoting benefits of natural cannabinoids. Cannabinoids can act via a variety of targets (GPR55, GPCR18, peroxisome proliferator-activated receptor gamma, serotonin receptors, etc.), their canonical targets are the cannabinoid CB1 and CB2 receptors. Both belong to the superfamily of G-protein-coupled-receptors (GPCRs) and both couple to the Gi heterotrimeric protein, i.e., receptor activation leads to Gi-mediated deactivation of adenylyl cyclase and reduction of intracellular cAMP levels. The anti-obesity potential of targeting the CB2R has not yet been addressed
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