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

Chem Biol
Authors
Keywords
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.

Year of Publication
2015
Journal
Chem Biol
Volume
22
Issue
6
Pages
764-75
Date Published
2015 Jun 18
ISSN
1879-1301
URL
DOI
10.1016/j.chembiol.2015.05.012
PubMed ID
26091169
PubMed Central ID
PMC4507497
Links
Grant list
R21 DA038858 / DA / NIDA NIH HHS / United States
HHSN271201300017C / MH / NIMH NIH HHS / United States
R01 DA017204 / DA / NIDA NIH HHS / United States
P01 DA035764 / DA / NIDA NIH HHS / United States
U01 MH104974 / MH / NIMH NIH HHS / United States