TY - JOUR
T1 - Single Amino Acid Variation Underlies Species-Specific Sensitivity to Amphibian Skin-Derived Opioid-like Peptides
AU - Vardy, Eyal
AU - Sassano, Maria F.
AU - Rennekamp, Andrew J.
AU - Kroeze, Wesley K.
AU - Mosier, Philip D.
AU - Westkaemper, Richard B.
AU - Stevens, Craig W.
AU - Katritch, Vsevolod
AU - Stevens, Raymond C.
AU - Peterson, Randall T.
AU - Roth, Bryan L.
N1 - Publisher Copyright:
© 2015 Elsevier Ltd All rights reserved.
PY - 2015/6/20
Y1 - 2015/6/20
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84934953131&partnerID=8YFLogxK
U2 - 10.1016/j.chembiol.2015.05.012
DO - 10.1016/j.chembiol.2015.05.012
M3 - Article
C2 - 26091169
AN - SCOPUS:84934953131
SN - 1074-5521
VL - 22
SP - 764
EP - 775
JO - Chemistry and Biology
JF - Chemistry and Biology
IS - 6
ER -