Abstract:
:The μ-opioid receptor gene undergoes extensive alternative splicing to generate an array of splice variants. One group of splice variants excludes the first transmembrane (TM) domain and contains six TM domains. These 6TM variants are essential for the action of a novel class of analgesic drugs, including 3-iodobenzoyl-6β-naltrexamide, which is potent against a spectrum of pain models without exhibiting the adverse side effects of traditional opiates. The 6TM variants are also involved in analgesic action through other drug classes, including δ-opioid and κ-opioids and α2-adrenergic drugs. Of the five 6TM variants in mouse, mouse μ-opioid receptor (mMOR)-1G is abundant and conserved from rodent to human. In the present study, we demonstrate a new function of mMOR-1G in enhancing expression of the full-length 7TM μ-opioid receptor, mMOR-1. When coexpressed with mMOR-1 in a Tet-Off inducible CHO cell line, mMOR-1G has no effect on mMOR-1 mRNA expression but greatly increases mMOR-1 protein expression in a dose-dependent manner determined by opioid receptor binding and [35S] guanosine 5'-3-O-(thio)triphosphate binding. Subcellular fractionation analysis using OptiPrep density gradient centrifugation shows an increase of functional mMOR-1 receptor in plasma membrane-enriched fractions. Using a coimmunoprecipitation approach, we further demonstrate that mMOR-1G physically associates with mMOR-1 starting at the endoplasmic reticulum, suggesting a chaperone-like function. These data provide a molecular mechanism for how mMOR-1G regulates expression and function of the full-length 7TM μ-opioid receptor. SIGNIFICANCE STATEMENT: The current study establishes a novel function of mouse μ-opioid receptor (mMOR)-1G, a truncated splice variant with six transmembrane (TM) domains of the mouse μ-opioid receptor gene, in enhancing expression of the full-length 7TM mMOR-1 through a chaperone-like function.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Zhang T,Xu J,Pan YXdoi
10.1124/mol.120.119453subject
Has Abstractpub_date
2020-10-01 00:00:00pages
518-527issue
4eissn
0026-895Xissn
1521-0111pii
mol.120.119453journal_volume
98pub_type
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