The single nucleotide polymorphism A118G alters functional properties of the human mu opioid receptor

被引:167
作者
Kroslak, Thomas
LaForge, K. Steven
Gianotti, Robert J.
Ho, Ann
Nielsen, David A.
Kreek, Mary Jeanne
机构
[1] Laboratory of the Biology of Addictive Diseases, Rockefeller University, New York, NY
[2] Laboratory of the Biology of Addictive Diseases, Rockefeller University, New York, NY 10021
基金
英国生物技术与生命科学研究理事会;
关键词
G-protein coupled receptor expression; MOP-r; OPRM1; SNP;
D O I
10.1111/j.1471-4159.2007.04738.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The most common single nucleotide polymorphism in the coding region of the human mu opioid receptor gene is the A118G variant, an adenine to guanine transition at nucleoticle position 118 of the coding sequence of the gene. This polymorphism codes for an asparagine to aspartic acid substitution at amino acid 40 in the amino-terminus, thereby removing a potential extracellular glycosylation site. Using in vitro cellular expression assays, this variant has been reported to change binding of the endoenous agonist beta-endorphin and signaling of the receptor following binding of beta-endorphin. Three clinical studies report that A118G genotype affects opioid antagonist-mediated increases in cortisol levels. These studies demonstrate a functional role of this variant in responses to endogenous and exogenous opioids. To further characterize function, we expressed the prototype and variant receptors in two types of cells (human 293 embryonic kidney cells and Syrian hamster adenovirus-12-induced tumor cells). Stable expression of variant and prototype receptors was characterized by differences in levels of cell surface binding capacity (B-max), forskolin-induced cAMP accumulation, as well as agonist-induced accumulation of cAMP (EC50) for several agonists, but not for beta-endorphin. In contrast, transiently expressed variant receptors showed only a minor difference in cell surface binding capacity compared to the prototype, and no differences in cAMP EC50 values.
引用
收藏
页码:77 / 87
页数:11
相关论文
共 42 条
[1]   Increased attributable risk related to a functional μ-opioid receptor gene polymorphism in association with alcohol dependence in central Sweden [J].
Bart, G ;
Kreek, MJ ;
Ott, J ;
LaForge, KS ;
Proudnikov, D ;
Pollak, L ;
Heilig, M .
NEUROPSYCHOPHARMACOLOGY, 2005, 30 (02) :417-422
[2]   Nalmefene induced elevation in serum prolactin in normal human volunteers: Partial kappa opioid agonist activity? [J].
Bart, G ;
Schluger, JH ;
Borg, L ;
Ho, A ;
Bidlack, JM ;
Kreek, MJ .
NEUROPSYCHOPHARMACOLOGY, 2005, 30 (12) :2254-2262
[3]   Substantial attributable risk related to a functional mu-opioid receptor gene polymorphism in association with heroin addiction in central Sweden [J].
Bart, G ;
Heilig, M ;
LaForge, KS ;
Pollak, L ;
Leal, SM ;
Ott, J ;
Kreek, MJ .
MOLECULAR PSYCHIATRY, 2004, 9 (06) :547-549
[4]   A single nucleotide polymorphic mutation in the human μ-opioid receptor severely impairs receptor signaling [J].
Befort, K ;
Filliol, D ;
Décaillot, FM ;
Gavériaux-Ruff, C ;
Hoehe, MR ;
Kieffer, BL .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (05) :3130-3137
[5]   mu opioid receptor gene variants: lack of association with alcohol dependence [J].
Bergen, AW ;
Peterson, R ;
Kokoszka, J ;
Long, JC ;
Virkkunen, M ;
Linnoila, M ;
Goldman, D .
MOLECULAR PSYCHIATRY, 1997, 2 (06) :490-494
[6]   Human mu opioid receptor gene polymorphisms and vulnerability to substance abuse [J].
Berrettini, WH ;
Hoehe, MR ;
Ferraro, TN ;
DeMaria, PA ;
Gottheil, E .
ADDICTION BIOLOGY, 1997, 2 (03) :303-308
[7]   Effect of the A118G polymorphism on binding affinity, potency and agonist-mediated endocytosis, desensitization, and resensitization of the human mu-opioid receptor [J].
Beyer, A ;
Koch, T ;
Schröder, H ;
Schulz, S ;
Höllt, V .
JOURNAL OF NEUROCHEMISTRY, 2004, 89 (03) :553-560
[8]   Requirement of N-glycosylation of the prostaglandin E2 receptor EP3β for correct sorting to the plasma membrane but not for correct folding [J].
Böer, U ;
Neuschäfer-Rube, F ;
Möller, U ;
Püschel, GP .
BIOCHEMICAL JOURNAL, 2000, 350 :839-847
[9]   Single-nucleotide polymorphism in the human mu opioid receptor gene alters β-endorphin binding and activity:: Possible implications for opiate addiction [J].
Bond, C ;
LaForge, KS ;
Tian, MT ;
Melia, D ;
Zhang, SW ;
Borg, L ;
Gong, JH ;
Schluger, J ;
Strong, JA ;
Leal, SM ;
Tischfield, JA ;
Kreek, MJ ;
Yu, L .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (16) :9608-9613
[10]   Glycosylation of the calcitonin receptor-like receptor at Asn60 or Asn112 is important for cell surface expression [J].
Bühlmann, N ;
Aldecoa, A ;
Leuthäuser, K ;
Gujer, R ;
Muff, R ;
Fischer, JA ;
Born, W .
FEBS LETTERS, 2000, 486 (03) :320-324