ZFIN ID: ZDB-PUB-170214-166
Single Amino Acid Variation Underlies Species-Specific Sensitivity to Amphibian Skin-Derived Opioid-like Peptides
Vardy, E., Sassano, M.F., Rennekamp, A.J., Kroeze, W.K., Mosier, P.D., Westkaemper, R.B., Stevens, C.W., Katritch, V., Stevens, R.C., Peterson, R.T., Roth, B.L.
Date: 2015
Source: Chemistry & Biology   22: 764-75 (Journal)
Registered Authors: Peterson, Randall, Stevens, Craig
Keywords: none
MeSH Terms:
  • Amino Acid Sequence
  • Amphibians/metabolism*
  • Analgesics, Opioid/chemistry
  • Analgesics, Opioid/metabolism*
  • Animals
  • Behavior, Animal/drug effects
  • Binding Sites
  • Humans
  • Kinetics
  • Molecular Dynamics Simulation
  • Molecular Sequence Data
  • Oligopeptides/chemistry
  • Oligopeptides/metabolism
  • Opioid Peptides/chemistry
  • Opioid Peptides/metabolism
  • Peptides/chemistry
  • Peptides/metabolism*
  • Peptides/pharmacology
  • Protein Structure, Tertiary
  • Receptors, Opioid/chemistry
  • Receptors, Opioid/metabolism
  • Sequence Alignment
  • Skin/metabolism*
  • Species Specificity
  • Zebrafish/physiology
PubMed: 26091169 Full text @ Chem. Biol.
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.