TY - JOUR T1 - Identification of Four Novel Exon 5 Splice Variants of the Mouse μ-Opioid Receptor Gene: Functional Consequences of C-Terminal Splicing JF - Molecular Pharmacology JO - Mol Pharmacol SP - 866 LP - 875 DO - 10.1124/mol.105.011858 VL - 68 IS - 3 AU - Ying-Xian Pan AU - Jin Xu AU - Elizabeth Bolan AU - Howard S. Moskowitz AU - Mingming Xu AU - Gavril W. Pasternak Y1 - 2005/09/01 UR - http://molpharm.aspetjournals.org/content/68/3/866.abstract N2 - 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. ER -