Identification of four novel exon 5 splice variants of the mouse μ-opioid receptor gene: Functional consequences of C-terminal splicing Journal Article

Authors: Pan, Y. X.; Xu, J.; Bolan, E.; Moskowitz, H. S.; Xu, M.; Pasternak, G. W.
Article Title: Identification of four novel exon 5 splice variants of the mouse μ-opioid receptor gene: Functional consequences of C-terminal splicing
Abstract: The rat μ-opioid receptor clone in which novel exon 5 was found in the place of exon 4 (MOR-1B) was one of the first MOR-1 variants described. We now have identified the mouse homolog of the rat MOR-1B as well as four additional variants derived from splicing from exon 3 into different sites within exon 5. The sequences of all of the variants were identical except for the intracellular tip of the C terminus encoded by exon 5, where each variant predicted a unique amino acid sequence ranging from 2 to 39 amino acids. All of the mMOR-1B variants were selective for μ-opioids in receptor-binding assays, as anticipated, because they all have identical binding pockets defined by the transmembrane domains. However, the relative potency and efficacy of μ-agonists to each other varied from variant to variant in guanosine 5′-O-(3-[ 35S]thio)triphosphate-binding studies, as shown by morphine-6β-glucuronide, which was the most efficacious agent against mouse MOR-1B1 (mMOR-1B1) and the least efficacious agent against mMOR-1B2. mMOR-1B4 was quite unusual. Although mMOR-1B4 was μ-selective in receptor-binding studies and antagonists labeled mMOR-1B4 well, the binding affinities of most of the μ-agonists were far lower than those seen with mMOR-1, suggesting that the 39 amino acids at the C terminus of mMOR-1B4 influences the conformation of the receptor and its ligand recognition site itself either directly or through its interactions with other proteins. In conclusion, alterations in the amino acid sequence of the C terminus do not alter the μ-specificity of the receptor but they can influence the binding characteristics, efficacy, and potency of μ-opioids. Copyright © 2005 The American Society for Pharmacology and Experimental Therapeutics.
Keywords: controlled study; gene sequence; exon; exons; drug efficacy; nonhuman; binding affinity; protein domain; mouse; animals; mice; carboxy terminal sequence; protein protein interaction; protein binding; genetic variability; drug potency; drug specificity; prediction; dna; amino acid sequence; molecular sequence data; reverse transcriptase polymerase chain reaction; nucleotide sequence; rat; ligand; base sequence; amino acid; conformation; sequence homology; spliceosome; blotting, northern; genetic code; mu opiate receptor; mu opiate receptor agonist; mu opiate receptor antagonist; receptors, opioid, mu; isoprotein; drug binding; receptor binding; rna splicing; morphine 6 glucuronide; genetic identification; intracellular space; membrane; guanosine 5'-o-(3-thiotriphosphate); binding assay; guanosine 5' o (3 thiotriphosphate); sulfur 35
Journal Title: Molecular Pharmacology
Volume: 68
Issue: 3
ISSN: 0026-895X
Publisher: The American Society for Pharmacology and Experimental Therapeutics  
Date Published: 2005-09-01
Start Page: 866
End Page: 875
Language: English
DOI: 10.1124/mol.105.011858
PUBMED: 15939800
PROVIDER: scopus
Notes: --- - "Cited By (since 1996): 43" - "Export Date: 24 October 2012" - "CODEN: MOPMA" - "Molecular Sequence Numbers: GENBANK: AF167566, AF167567, AF346812, AF346813, AY390763;" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Elizabeth A Bolan
    18 Bolan
  2. Yingxian Pan
    108 Pan
  3. Gavril W Pasternak
    296 Pasternak
  4. Ming Ming Xu
    34 Xu
  5. Jin   Xu
    50 Xu