Abstract
Two cannabinoid (CB) receptors are known in humans,
CB1 and CB2. They are phylogenetically ancient. Studies suggest CB receptors
occur in mammals, birds, amphibians, fish, sea urchins, mollusks,
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 million
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 obtained
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-
lective constraints, subsequently acquired a mutation that coupled them
with 2-AG. A better understanding of CB and VR receptors man enable
us to combine their beneficial effects. Dual-signaling ligands such as
anandamide have excellent therapeutic potential as analgesics, vasodilators,
and anti-cancer agents.
Keywords. Cannabis, cannabinoids, vanilloids, G-protein coupled
receptors, anandamide, horizontal gene transfer