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

Eyal Vardy, Maria F. Sassano, Andrew J. Rennekamp, Wesley K. Kroeze, Philip D. Mosier, Richard B. Westkaemper, Craig W. Stevens, Vsevolod Katritch, Raymond C. Stevens, Randall T. Peterson, Bryan L. Roth

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)764-775
Number of pages12
JournalChemistry and Biology
Volume22
Issue number6
DOIs
StatePublished - 20 Jun 2015

Fingerprint

Opioid Peptides
Opioid Receptors
Amphibians
Opioid Analgesics
Skin
Anura
Amino Acids
Peptides
Fish
Fishes
Lampreys
delta Opioid Receptor
Molecular modeling
Leucine
Vertebrates
Phenotype
deltorphin

Cite this

Vardy, E., Sassano, M. F., Rennekamp, A. J., Kroeze, W. K., Mosier, P. D., Westkaemper, R. B., ... Roth, B. L. (2015). Single Amino Acid Variation Underlies Species-Specific Sensitivity to Amphibian Skin-Derived Opioid-like Peptides. Chemistry and Biology, 22(6), 764-775. https://doi.org/10.1016/j.chembiol.2015.05.012
Vardy, Eyal ; Sassano, Maria F. ; Rennekamp, Andrew J. ; Kroeze, Wesley K. ; Mosier, Philip D. ; Westkaemper, Richard B. ; Stevens, Craig W. ; Katritch, Vsevolod ; Stevens, Raymond C. ; Peterson, Randall T. ; Roth, Bryan L. / Single Amino Acid Variation Underlies Species-Specific Sensitivity to Amphibian Skin-Derived Opioid-like Peptides. In: Chemistry and Biology. 2015 ; Vol. 22, No. 6. pp. 764-775.
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Vardy, E, Sassano, MF, Rennekamp, AJ, Kroeze, WK, Mosier, PD, Westkaemper, RB, Stevens, CW, Katritch, V, Stevens, RC, Peterson, RT & Roth, BL 2015, 'Single Amino Acid Variation Underlies Species-Specific Sensitivity to Amphibian Skin-Derived Opioid-like Peptides', Chemistry and Biology, vol. 22, no. 6, pp. 764-775. https://doi.org/10.1016/j.chembiol.2015.05.012

Single Amino Acid Variation Underlies Species-Specific Sensitivity to Amphibian Skin-Derived Opioid-like Peptides. / Vardy, Eyal; Sassano, Maria F.; Rennekamp, Andrew J.; Kroeze, Wesley K.; Mosier, Philip D.; Westkaemper, Richard B.; Stevens, Craig W.; Katritch, Vsevolod; Stevens, Raymond C.; Peterson, Randall T.; Roth, Bryan L.

In: Chemistry and Biology, Vol. 22, No. 6, 20.06.2015, p. 764-775.

Research output: Contribution to journalArticle

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