Internal Med Medical News about mu-opioid receptor gene;human variants

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Functional characterization of human variants of the mu-opioid receptor gene
Proceedings of the National Academy of Sciences of the United States of America, 07/02/09

Ravindranathan A et al. – Data suggest that S42T, C192F, and S147C variants and other such variants may have clinical relevance to opioid responsiveness to both endogenous ligands and exogenous drugs, and may influence a broad range of phenotypes, including alcohol and substance use disorders (ASUD), pain responses, and development of tolerance to morphine.

Methods

For several naturally occurring amino acid changing variants of the human mu-opioid receptor (MOR), study of the functional consequences of these previously undescribed variants in stably expressing cell lines

Results

In response to morphine, significant internalization for an L85I variant vs no internalization for WT MOR
On L85I and WT receptor coexpression, WT MOR internalized with L85I MOR, suggesting dominant L85I phenotype in a heterozygous condition
Finding potentially important as receptor internalization is associated with development of tolerance to opiate analgesics
An R181C variant abolished both signaling and internalization in response to saturating doses of the hydrolysis-resistant enkephalin [D-Ala2,N-MePhe4,Gly5-ol]enkephalin (DAMGO)
R181C and WT receptor coexpression led to independent trafficking of the 2 receptors
S42T and C192F variants: rightward shift in potency of both morphine and DAMGO
S147C variant: subtle leftward shift in morphine potency

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