Species differences in cannabinoid receptor 2 (CNR2 gene): identification of novel human and rodent CB2 isoforms, differential tissue expression and regulation by cannabinoid receptor ligands

Abstract

Cannabinoids, endocannabinoids and marijuana activate two well-characterized cannabinoid receptors (CB-Rs), CB1-Rs and CB2-Rs. The expression of CB1-Rs in the brain and periphery has been well studied, but neuronal CB2-Rs have received much less attention than CB1-Rs. Many studies have now identified and characterized functional glial and neuronal CB2-Rs in the central nervous system. However, many features of CB2-R gene structure, regulation and variation remain poorly characterized in comparison with the CB1-R. In this study, we report on the discovery of a novel human CB2 gene promoter transcribing testis (CB2A) isoform with starting exon located ca 45 kb upstream from the previously identified promoter transcribing the spleen isoform (CB2B). The 5 exons of both CB2 isoforms are untranslated 5 UTRs and alternatively spliced to the major protein coding exon of the CB2 gene. CB2A is expressed higher in testis and brain than CB2B that is expressed higher in other peripheral tissues than CB2A. Species comparison found that the CB2 gene of human, rat and mouse genomes deviated in their gene structures and isoform expression patterns. mCB2A expression was increased significantly in the cerebellum of mice treated with the CB-R mixed agonist, WIN55212-2. These results provide much improved information about CB2 gene structure and its human and rodent variants that should be considered in developing CB2-R-based therapeutic agents.

Neuronal expression of CB2 cannabinoid receptor mRNAs in the mouse hippocampus

“…The data also showed that the mRNA levels of CB2R-B in the hippocampus were almost undetectable (Fig. 1A), in accord with the results from other brain areas such as the prefrontal cortex, striatum and brain stem (Liu et al, 2009). …”

“…Two pairs of primers were designed to detect two splicing variants, which have been named CB2R-A (NM_009924.3) and CB2R-B (XM_006538515.1) (Liu et al, 2009) (Fig. 1A).…”

Disease modification of breast cancer–induced bone remodeling by cannabinoid 2 receptor agonists

“…However, recent findings also suggest alternative receptor coupling of the CB 2 receptor or unidentified cannabinoid receptors and splice variants. (77) The difficulty of determining that effects are in fact specifically cannabinoid receptor–mediated is complicated by the constitutive activity of both cannabinoid receptors that may sustain biological processes, and a lack of neutral antagonists for both receptors. Future studies are likely to determine the molecular pathway in which CB 2 agonists successfully inhibit breast cancer proliferation and cytokine-chemokine secretion.…”

Alternative Splicing of G Protein–Coupled Receptors: Relevance to Pain Management

“…The CB 2 variants are generated through the use of alternate promoters located upstream of the major coding exon 3 53 . The gene CB 2A is initiated from the more distal promoter and includes exons 1a and 1b spliced to exon 3, while CB 2B is initiated from the more proximal promoter and includes exon 2 spliced to exon 3.…”