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Phylogenomic and chemotaxonomic analysis of the endocannabinoid system.

Abstract

The endocannabinoid system consists of two cannabinoid (CB) receptors, seven ligands, and ligand-catabolizing enzymes such as fatty acid amid hydrolase (FAAH) and monoglyceride lipase (MGL). The system's phylogenetic distribution is poorly known. The ligands cannot be molecularly investigated because they are not polypeptides and their specific synthetic enzymes have not been identified, so no sequences are available. Ligand phylogenetics can be inferred, nonetheless, by their presence in a range of extant organisms. Thus a meta-analysis of ligand extraction studies was performed (chemotaxonomy), and compared to a molecular search for homologs of CB receptors, vanilloid receptors (VR1), FAAH, and MGL in the genomes of sequenced organisms (phylogenomics). Putative homologs underwent functional mapping to ascertain the presence of critical amino acid motifs known to impart protein functionality. From an evolutionary perspective it appears that (1) endocannabinoid ligands evolved before CB receptors; (2) the ligands evolved independently multiple times; (3) CB receptors evolved prior to the metazoan-bilaterian divergence (ie, between extant Hydra and leech), but were secondarily lost in the Ecdysozoa; (4) VR1 may predate CB receptors but its affinity for endocannabinoids is a recent acquisition, appearing after the lower vertebrate-mammal divergence; (5) MGL may be as old as the ligands, whereas FAAH evolved recently, after the appearance of vertebrates. FAAH's emergence correlates with VR1's newly-found affinity for anandamide; this overlap in evolutionary time is recapitulated by complementary distribution patterns of FAAH, VR1, and anandamide in the brain. Linking FAAH, VR1, and anandamide implies a coupling among the remaining "older" parts of the endocannabinoid system, MGL, CB receptors, and 2-AG.

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  • Publisher Full Text
  • Authors+Show Affiliations

    GW Pharmaceuticals Ltd., Porton Down Science Park, Salisbury, Wiltshire SP4 0JQ, UK. jmcpartland@unitec.ac.nz

    Source

    MeSH

    Amidohydrolases
    Animals
    Cannabinoid Receptor Modulators
    Classification
    Endocannabinoids
    Humans
    Meta-Analysis as Topic
    Monoacylglycerol Lipases
    Phylogeny
    Receptors, Cannabinoid
    Receptors, Drug

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't
    Review

    Language

    eng

    PubMed ID

    15063097

    Citation

    McPartland, John M.. "Phylogenomic and Chemotaxonomic Analysis of the Endocannabinoid System." Brain Research. Brain Research Reviews, vol. 45, no. 1, 2004, pp. 18-29.
    McPartland JM. Phylogenomic and chemotaxonomic analysis of the endocannabinoid system. Brain Res Brain Res Rev. 2004;45(1):18-29.
    McPartland, J. M. (2004). Phylogenomic and chemotaxonomic analysis of the endocannabinoid system. Brain Research. Brain Research Reviews, 45(1), pp. 18-29.
    McPartland JM. Phylogenomic and Chemotaxonomic Analysis of the Endocannabinoid System. Brain Res Brain Res Rev. 2004;45(1):18-29. PubMed PMID: 15063097.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Phylogenomic and chemotaxonomic analysis of the endocannabinoid system. A1 - McPartland,John M, PY - 2003/11/04/accepted PY - 2004/4/6/pubmed PY - 2004/6/29/medline PY - 2004/4/6/entrez SP - 18 EP - 29 JF - Brain research. Brain research reviews JO - Brain Res. Brain Res. Rev. VL - 45 IS - 1 N2 - The endocannabinoid system consists of two cannabinoid (CB) receptors, seven ligands, and ligand-catabolizing enzymes such as fatty acid amid hydrolase (FAAH) and monoglyceride lipase (MGL). The system's phylogenetic distribution is poorly known. The ligands cannot be molecularly investigated because they are not polypeptides and their specific synthetic enzymes have not been identified, so no sequences are available. Ligand phylogenetics can be inferred, nonetheless, by their presence in a range of extant organisms. Thus a meta-analysis of ligand extraction studies was performed (chemotaxonomy), and compared to a molecular search for homologs of CB receptors, vanilloid receptors (VR1), FAAH, and MGL in the genomes of sequenced organisms (phylogenomics). Putative homologs underwent functional mapping to ascertain the presence of critical amino acid motifs known to impart protein functionality. From an evolutionary perspective it appears that (1) endocannabinoid ligands evolved before CB receptors; (2) the ligands evolved independently multiple times; (3) CB receptors evolved prior to the metazoan-bilaterian divergence (ie, between extant Hydra and leech), but were secondarily lost in the Ecdysozoa; (4) VR1 may predate CB receptors but its affinity for endocannabinoids is a recent acquisition, appearing after the lower vertebrate-mammal divergence; (5) MGL may be as old as the ligands, whereas FAAH evolved recently, after the appearance of vertebrates. FAAH's emergence correlates with VR1's newly-found affinity for anandamide; this overlap in evolutionary time is recapitulated by complementary distribution patterns of FAAH, VR1, and anandamide in the brain. Linking FAAH, VR1, and anandamide implies a coupling among the remaining "older" parts of the endocannabinoid system, MGL, CB receptors, and 2-AG. UR - https://www.unboundmedicine.com/medline/citation/15063097/Phylogenomic_and_chemotaxonomic_analysis_of_the_endocannabinoid_system_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0165017304000037 DB - PRIME DP - Unbound Medicine ER -