Genes encoding marijuana receptors and their chromosomal localization

Cannabinoids are the constituents of the marijuana plant (cannabis saliva). Recent advances include the cloning of the cDNA encoding the rat, human and the mouse CNS (CB1, CB1A) and the peripheral (CB2) cannabinoid receptors (Cnrs). A putative ligand, anandamide, thought to represent the endogenous cannabis-like substance in the brain and an antagonist, SR141716A. that binds the Cms have been identified. We cloned, sequenced, constructed the 3D model and localized the mouse CB1 Cnr gene to chromsome 4. In comparison to the rat and human CB1 sequences, the mouse CB1 gene showed extensive nucleotide and protein sequence homology. The mammalian CB1 Cnrs share many of the conserved residues of the G-protein coupled receptors with similar transmembrane helix bundle arrangement and some stricking differences. The results of the chromosomal location of the human and mouse CB1 genes adds a new marker to the region of the human 6q genes of mouse-human homology and confirms the close linkage of CB1 genes in both species. Although there are no obvious connections between the positions established for the CB] gene and mutations mapped to this region, the biological effects of cannabinolds in mammalian systems predict that mutations in the Cnr locus should prove fascinating, and valuable as animal models for human drug abuse, pain perception, mental and neurological dysfunction and in other disorders. An understanding of the in vivo role of cannabinoids and their receptors may require the creation and careful analysis of targeted gene mutations in mice. Supported by NSFMRCE HRD-9255157, RCMI NIH 5O12RR0303208, US-DOE contract AC05-840R21400 with Lockheed-Martin Energy systems.