Single-nucleotide polymorphism in the human mu opioid receptor gene alters β-endorphin binding and activity:: Possible implications for opiate addiction
Single-nucleotide polymorphism in the human mu opioid receptor gene alters β-endorphin binding and activity:: Possible implications for opiate addiction
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DOI：
10.1073/pnas.95.16.9608
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发表时间：
1998-08-04
影响因子：
11.1
通讯作者：
Yu, L
中科院分区：
文献类型：
--
作者：
Bond, C;LaForge, KS;Yu, L
阿片类药物在疼痛的临床治疗以及药物滥用的发展和治疗中发挥着重要作用。 mu 阿片受体是最常用阿片类药物（包括吗啡、海洛因、芬太尼和美沙酮）的主要作用位点。通过对 113 名美沙酮维持治疗前海洛因成瘾者和 39 名无药物或酒精滥用或依赖史的个体的 DNA 进行测序，我们在 mu 阿片受体基因的编码区中鉴定出了 5 种不同的单核苷酸多态性 (SNP)，最常见的 SNP 是第 118 位的核苷酸取代 (A118G)，预测假定的 N-糖基化位点的氨基酸变化。该 SNP 在我们的研究人群中显示等位基因频率约为 10%，在所研究的种族群体之间观察到等位基因分布的显着差异。 A118G SNP 产生的变异受体对大多数测试的阿片肽和生物碱没有显示出改变的结合亲和力。然而，A118G变体受体与β-内啡肽（一种激活μ阿片受体的内源性阿片类药物）的结合强度大约是该受体最常见等位基因形式的三倍。此外，在激动剂诱导的G蛋白偶联钾通道激活中，β-内啡肽对A118G变体受体的效力大约是最常见等位基因形式的三倍。这些结果表明，mu 阿片受体基因中的 SNP 可以改变所得受体的结合和信号转导，并可能对正常生理、治疗以及对包括成瘾性疾病在内的多种疾病的易感性和预防产生影响。
Opioid drugs play important roles in the clinical management of pain, as well as in the development and treatment of drug abuse. The mu opioid receptor is the primary site of action for the most commonly used opioids, including morphine, heroin, fentanyl, and methadone. By sequencing DNA from 113 former heroin addicts in methadone maintenance and 39 individuals with no history of drug or alcohol abuse or dependence, we have identified five different single-nucleotide polymorphisms (SNPs) in the coding region of the mu opioid receptor gene, The most prevalent SNP is a nucleotide substitution at position 118 (A118G), predicting an amino acid change at a putative N-glycosylation site. This SNP displays an allelic frequency of approximately 10% in our study population, Significant differences in allele distribution were observed among ethnic groups studied. The variant receptor resulting from the A118G SNP did not show altered binding affinities for most opioid peptides and alkaloids tested. However, the A118G variant receptor binds beta-endorphin, an endogenous opioid that activates the mu opioid receptor, approximately three times more tightly than the most common allelic form of the receptor, Furthermore, beta-endorphin is approximately three times more potent at the A118G variant receptor than at the most common allelic form in agonist-induced activation of G protein-coupled potassium channels. These results show that SNPs in the mu opioid receptor gene can alter binding and signal transduction in the resulting receptor and may have implications for normal physiology, therapeutics, and vulnerability to develop or protection from diverse diseases including the addictive diseases.