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Cannabinoid Receptor Genetics and Evolution

Cannabinoid Receptor Genetics and Evolution

  1. ThirdEyeFloond
    The Cannabinoid Receptors p123-149

    Maurice R. Elphick and Michaela Egertov√°

    Abstract
    The G-protein cannabinoid receptors CB1 and CB2 mediate effects of Cannabis-derived, synthetic and endogenous cannabinoids in humans and other mammals. Identification of the genes that encode CB1 and CB2 has facilitated utilisation of genetic strategies for pharmacological, physiological, behavioural and pathological characterisation of cannabinoid receptor function. For example, analysis of systemic or conditional CB1-knockout mice has demonstrated that CB1 is required for endocannabinoid-mediated retrograde signalling at synapses in the brain and that CB1 expression in forebrain principal neurons mediates protection against seizures. Evidence of a role for CB2 in protection against osteoporosis has emerged from analysis of polymorphisms in the human CB2 gene and analysis of bone mass in CB2-knockout mice.
    CB1 and CB2 share sequence similarity indicative of a common ancestry and the gene duplication that gave rise to these cannabinoid receptors may have been concomitant with a whole-genome duplication that occurred in a common ancestor of extant vertebrates. Accordingly, CB1 and CB2 genes have also been identified in a variety of non-mammalian vertebrates (birds, amphibians and teleost fish). Another genome duplication in a common ancestor of teleost fish followed by lineage-specific gene loss probably explains the occurrence of two CB1 genes and one CB2 gene in the puffer fish Fugu rubripes and the occurrence of one CB1 gene and two CB2 genes in the zebrafish Danio rerio. Identification of CB1 and CB2 genes in non-mammalian vertebrates has enabled comparative analysis of the expression and functions of these genes in a variety of vertebrate species and several non-mammalian vertebrates are emerging as model systems for cannabinoid research.
    Investigation of the phylogenetic distribution and evolutionary origins of cannabinoid receptors has been facilitated by genome sequencing. However, absence of orthologs of CB1/CB2 receptors in protostomian invertebrates (Drosophila melanogaster, Caenorhabditis elegans) and in the deuterostomian invertebrate Strongylocentrotus purpuratus (sea urchin) indicates that CB1/CB2-related cannabinoid receptors do not occur in the majority of invertebrates. Identification of an ortholog of vertebrate CB1/CB2 receptors known as CiCBR in the sea squirt Ciona intestinalis (subphylum Urochordata) indicates that cannabinoid receptors of this type originated in an invertebrate chordate ancestor of vertebrates and urochordates. Because CiCBR is the first putative cannabinoid receptor to be identified in an invertebrate, discovery of this receptor has provided a unique opportunity to investigate cannabinoid receptor function in an invertebrate species. Analysis of Ciona may provide an insight into the ancestral physiological roles of cannabinoid receptors in invertebrate chordates prior to the gene duplication that gave rise to CB1 and CB2 receptors in vertebrates.