title: Stabilization of the μ-opioid receptor by truncated single transmembrane splice variants through a chaperone-like action.
abstract: The μ-opioid receptor gene, OPRM1, undergoes extensive alternative pre-mRNA splicing, as illustrated by the identification of an array of splice variants generated by both 5' and 3' alternative splicing. The current study reports the identification of another set of splice variants conserved across species that are generated through exon skipping or insertion that encodes proteins containing only a single transmembrane (TM) domain. Using a Tet-Off system, we demonstrated that the truncated single TM variants can dimerize with the full-length 7-TM μ-opioid receptor (MOR-1) in the endoplasmic reticulum, leading to increased expression of MOR-1 at the protein level by a chaperone-like function that minimizes endoplasmic reticulum-associated degradation. In vivo antisense studies suggested that the single TM variants play an important role in morphine analgesia, presumably through modulation of receptor expression levels. Our studies suggest the functional roles of truncated receptors in other G protein-coupled receptor families.
authors.affiliation: From the Department of Neurology and the Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065.
authors.forename: Jin
authors.initials: J
authors.lastname: Xu
authors.affiliation: From the Department of Neurology and the Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065.
authors.forename: Ming
authors.initials: M
authors.lastname: Xu
authors.affiliation: From the Department of Neurology and the Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065.
authors.forename: Taylor
authors.initials: T
authors.lastname: Brown
authors.affiliation: the Department of Psychology, CW Post College, Long Island University, Brookville, New York 11568.
authors.forename: Grace C
authors.initials: GC
authors.lastname: Rossi
authors.affiliation: the Department of Psychiatry and Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, New York 10029, and.
authors.forename: Yasmin L
authors.initials: YL
authors.lastname: Hurd
authors.affiliation: the Department of Pharmacology, Weill Cornell Medical College, New York, New York 10065.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Inturrisi
authors.affiliation: From the Department of Neurology and the Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065,; the Department of Pharmacology, Weill Cornell Medical College, New York, New York 10065. Electronic address: pasterng@mskcc.org.
authors.forename: Gavril W
authors.initials: GW
authors.lastname: Pasternak
authors.affiliation: From the Department of Neurology and the Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065,. Electronic address: pany@mskcc.org.
authors.forename: Ying-Xian
authors.initials: YX
authors.lastname: Pan
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D020126:Brefeldin A / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism*; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D020869:Gene Expression Profiling; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D006801:Humans; D051379:Mice; D018832:Molecular Chaperones / Q000378:metabolism*; D009020:Morphine / Q000494:pharmacology; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011485:Protein Binding; D055503:Protein Multimerization; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017450:Receptors, Opioid, mu / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D018076:DNA, Complementary; D018832:Molecular Chaperones; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D020126:Brefeldin A; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D009020:Morphine
keywords: Alternative Splicing; Analgesia; Antisense Oligodeoxynucleotide; Dimerization; G Protein-coupled Receptors (GPCR); Molecular Chaperone; Morphine; Opiate Opioid; Receptor Regulation