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      Single Amino Acid Variation Underlies Species-Specific Sensitivity to Amphibian Skin-Derived Opioid-like Peptides.

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          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.

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          Author and article information

          Journal
          Chem. Biol.
          Chemistry & biology
          Elsevier BV
          1879-1301
          1074-5521
          Jun 18 2015
          : 22
          : 6
          Affiliations
          [1 ] Department of Pharmacology, UNC Chapel Hill Medical School, 4072 Genetic Medicine Building, 120 Mason Farm Road, Chapel Hill, NC 27514, USA.
          [2 ] 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.
          [3 ] Department of Medicinal Chemistry, Virginia Commonwealth University School of Pharmacy, Richmond, VA 23298, USA.
          [4 ] Department of Pharmacology & Physiology, Oklahoma State University Center for Health Sciences, 1111 West 17(th) Street, Tulsa, OK 74107, USA.
          [5 ] Department of Biological Sciences and Chemistry, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA.
          [6 ] 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.
          Article
          S1074-5521(15)00196-9 NIHMS696741
          10.1016/j.chembiol.2015.05.012
          4507497
          26091169
          6b6d366f-4dca-4ae3-8a55-a26e9417ca99
          History

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