期刊
CHEMISTRY & BIOLOGY
卷 22, 期 6, 页码 764-775出版社
CELL PRESS
DOI: 10.1016/j.chembiol.2015.05.012
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资金
- NIDA NIH HHS [R33 DA038858, R21 DA038858, P01 DA035764, R01 DA017204] Funding Source: Medline
- NIMH NIH HHS [U01 MH104974, HHSN271201300017C] Funding Source: Medline
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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