title: Single Amino Acid Variation Underlies Species-Specific Sensitivity to Amphibian Skin-Derived Opioid-like Peptides.
abstract: It has been suggested that the evolution of vertebrate opioid receptors (ORs) follow a vector of increased functionality. Here, we test this idea by comparing human and frog ORs. Interestingly, some of the most potent opioid peptides known have been isolated from amphibian skin secretions. Here we show that such peptides (dermorphin and deltorphin) are highly potent in the human receptors and inactive in frog ORs. The molecular basis for the insensitivity of the frog ORs to these peptides was studied using chimeras and molecular modeling. The insensitivity of the delta OR (DOR) to deltorphin was due to variation of a single amino acid, Trp7.35, which is a leucine in mammalian DORs. Notably, Trp7.35 is completely conserved in all known DOR sequences from lamprey, fish, and amphibians. The deltorphin-insensitive phenotype was verified in fish. Our results provide a molecular explanation for the species selectivity of skin-derived opioid peptides.
authors.affiliation: Department of Pharmacology, UNC Chapel Hill Medical School, 4072 Genetic Medicine Building, 120 Mason Farm Road, Chapel Hill, NC 27514, USA.
authors.forename: Eyal
authors.initials: E
authors.lastname: Vardy
authors.affiliation: Department of Pharmacology, UNC Chapel Hill Medical School, 4072 Genetic Medicine Building, 120 Mason Farm Road, Chapel Hill, NC 27514, USA.
authors.forename: Maria F
authors.initials: MF
authors.lastname: Sassano
authors.affiliation: Cardiovascular Research Center and Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 149 13(th) Street, Charlestown, MA 02129, USA; Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Rennekamp
authors.affiliation: Department of Pharmacology, UNC Chapel Hill Medical School, 4072 Genetic Medicine Building, 120 Mason Farm Road, Chapel Hill, NC 27514, USA.
authors.forename: Wesley K
authors.initials: WK
authors.lastname: Kroeze
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University School of Pharmacy, Richmond, VA 23298, USA.
authors.forename: Philip D
authors.initials: PD
authors.lastname: Mosier
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University School of Pharmacy, Richmond, VA 23298, USA.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Westkaemper
authors.affiliation: Department of Pharmacology & Physiology, Oklahoma State University Center for Health Sciences, 1111 West 17(th) Street, Tulsa, OK 74107, USA.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Stevens
authors.affiliation: Department of Biological Sciences and Chemistry, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Vsevolod
authors.initials: V
authors.lastname: Katritch
authors.affiliation: Department of Biological Sciences and Chemistry, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Stevens
authors.affiliation: Cardiovascular Research Center and Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, 149 13(th) Street, Charlestown, MA 02129, USA; Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Randall T
authors.initials: RT
authors.lastname: Peterson
authors.affiliation: Department of Pharmacology, UNC Chapel Hill Medical School, 4072 Genetic Medicine Building, 120 Mason Farm Road, Chapel Hill, NC 27514, USA. Electronic address: bryan_roth@med.unc.edu.
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
mesh_terms: D000595:Amino Acid Sequence; D000663:Amphibians / Q000378:metabolism*; D000701:Analgesics, Opioid / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001665:Binding Sites; D006801:Humans; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism; D018847:Opioid Peptides / Q000737:chemistry / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011957:Receptors, Opioid / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D012867:Skin / Q000378:metabolism*; D013045:Species Specificity; D015027:Zebrafish / Q000502:physiology
chemical_list: D000701:Analgesics, Opioid; D009842:Oligopeptides; D018847:Opioid Peptides; D010455:Peptides; D011957:Receptors, Opioid; C059567:deltorphin; C030058:dermorphin