Identification of Four Novel Exon 5 Splice Variants of the Mouse μ-Opioid Receptor Gene: Functional Consequences of C-Terminal Splicing
Open Access
- 6 June 2005
- journal article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in Molecular Pharmacology
- Vol. 68 (3), 866-875
- https://doi.org/10.1124/mol.105.011858
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.Keywords
This publication has 41 references indexed in Scilit:
- Functional analysis of MOR‐1 splice variants of the mouse mu opioid receptor gene OprmSynapse, 2003
- Presynaptic localization of the carboxy-terminus epitopes of the μ opioid receptor splice variants MOR-1C and MOR-1D in the superficial laminae of the rat spinal cordNeuroscience, 2001
- Strategies to Manage the Adverse Effects of Oral Morphine: An Evidence-Based ReportJournal of Clinical Oncology, 2001
- Comparative immunohistochemical distributions of carboxy terminus epitopes from the mu-opioid receptor splice variants MOR-1D, MOR-1 and MOR-1C in the mouse and rat CNSNeuroscience, 2000
- Oligomerization of μ- and δ-Opioid ReceptorsJournal of Biological Chemistry, 2000
- The Regulator of G Protein Signaling FamilyAnnual Review of Pharmacology and Toxicology, 2000
- Differential distribution in rat brain of mu opioid receptor carboxy terminal splice variants MOR-1C-like and MOR-1-like immunoreactivity: Evidence for region-specific processingJournal of Comparative Neurology, 2000
- Expression of two variants of the human μ opioid receptor mRNA in SK‐N‐SH cells and human brainFEBS Letters, 1994
- Guanine nucleotides differentiate agonist and antagonist interactions with opiate receptorsLife Sciences, 1978
- ACTIONS OF ETORPHINE HYDROCHLORIDE, (M99): A POTENT MORPHINE‐LIKE AGENTBritish Journal of Pharmacology and Chemotherapy, 1967