Proenkephalin A gene products activate a new family of sensory neuron--specific GPCRs.
Several peptide fragments are produced by proteolytic cleavage of the opioid peptide precursor proenkephalin A, and among these are a number of enkephalin fragments, in particular bovine adrenal medulla peptide 22 (BAM22). These peptide products have been implicated in diverse biological functions, including analgesia. We have cloned a newly identified family of 'orphan' G protein--coupled receptors (GPCRs) and demonstrate that BAM22 and a number of its fragments bind to and activate these receptors with nanomolar affinities. This family of GPCRs is uniquely localized in the human and rat small sensory neuron, and we called this family the sensory neuron--specific G protein--coupled receptors (SNSRs). Receptors of the SNSR family are distinct from the traditional opioid receptors in their insensitivity to the classical opioid antagonist naloxone and poor activation by opioid ligands. The unique localization of SNSRs and their activation by proenkephalin A peptide fragments indicate a possible function for SNSRs in sensory neuron regulation and in the modulation of nociception.
Lembo
Paola M C
PM
AstraZeneca R&D Montreal, 7171 Frederick-Banting, Ville Saint-Laurent, Quebec H4S 1Z9, Canada. paola.lembo@astrazeneca.com
Grazzini
Eric
E
Groblewski
Thierry
T
O'Donnell
Dajan
D
Roy
Marie-Odile
MO
Zhang
Ji
J
Hoffert
Cyrla
C
Cao
Jack
J
Schmidt
Ralf
R
Pelletier
Manon
M
Labarre
Maryse
M
Gosselin
Mylene
M
Fortin
Yves
Y
Banville
Denis
D
Shen
S H
SH
Ström
Peter
P
Payza
Kemal
K
Dray
Andy
A
Walker
Philippe
P
Ahmad
Sultan
S
D000595:Amino Acid Sequence; D000818:Animals; D001923:Brain Chemistry; D002118:Calcium / Q000378:metabolism; D004622:Embryo, Mammalian / Q000502:physiology; D004745:Enkephalins / Q000235:genetics / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism; D006801:Humans; D017403:In Situ Hybridization; D008024:Ligands; D008969:Molecular Sequence Data; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism*; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism*; D018847:Opioid Peptides / Q000378:metabolism; D010802:Phylogeny; D011485:Protein Binding; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D014018:Tissue Distribution
D004745:Enkephalins; D008024:Ligands; D009292:Narcotic Antagonists; D018847:Opioid Peptides; D011498:Protein Precursors; D011956:Receptors, Cell Surface; C029992:proenkephalin; D009270:Naloxone; D019204:GTP-Binding Proteins; D002118:Calcium