Sourcing the Code

Abstract

Two cannabinoid (CB) receptors are known in humans, CB 1 and CB 2 . They are phylogenetically ancient. Studies suggest CB re- ceptors occur in mammals, birds, amphibians, fish, sea urchins, mol- lusks, leeches, and Hydra vulgaris. The CB receptor genes from some of these animals have been cloned and sequenced. These sequences were used to construct a phylogenetic tree of CB genes. The gene tree is rooted in an ancestral CB gene that predates the divergence of vertebrates and invertebrates. Thus the primordial CB receptor evolved at least 600 mil- lion years ago, a date broadly consistent with the Cambrian explosion. Since then, one clade of invertebrates, the Ecdysozoa, has secondarily lost the genes coding CB receptors. There is no evidence that animals ob- tained CB genes from other organisms via horizontal gene transfer. We hypothesize that the primordial CB receptor diverged from a related G-protein coupled receptor, and it linked with a pre-existing ligand, anandamide. Anandamide serves as a ligand for CB receptors as well as vanilloid (VR) receptors. VR receptors regulate the sensation of pain, and may also modulate mood and memory. Our phylogenetic analysis suggests that VR receptors evolved before CB receptors, so anandamide first served as a VR ligand. We speculate that CB receptors, lacking se-