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首页> 外文期刊>American Journal of Physiology >Variable-length poly-C tract polymorphisms of the beta2-adrenergic receptor 3'-UTR alter expression and agonist regulation
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Variable-length poly-C tract polymorphisms of the beta2-adrenergic receptor 3'-UTR alter expression and agonist regulation

机译：beta2-肾上腺素受体3'-UTR的可变长度多C链多态性改变表达和激动剂调节。

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First published November 16, 2007; doi:10.1152/ajplung.00277.2007.-dollar2-Adrenergic receptors (beta2-AR) expressed on airway epithelial and smooth muscle cells regulate mucociliary clearance and relaxation and are the targets for beta-agonists in the treatment of obstructive lung disease. However, the clinical responses display extensive interindi-vidual variability, which is not adequately explained by genetic variability in the 5'-flanking or coding region of the intronless beta2-AR gene. The nonsynonymous coding polymorphism most often associated with a bronchodilator phenotype (Argl6) is found within three haplotypes that differ by the number of Cs (11, 12, or 13) within a 3'-untranslated region (UTR) poly-C tract. To examine potential effects of this variability on receptor expression, BEAS-2B cells were transfected with constructs containing the beta2-AR (Argl6) coding sequence followed by its 3'-UTR with the various polymorphic poly-C tracts. beta2Argl6-HC had 25% lower mRNA expression and 33%lower beta2-AR protein expression compared with the other two haplotypes. Consistent with this lower steady-state expression, beta2Argl6-l 1C mRNA displayed more rapid and extensive degradation after actinomycin D treatment compared with beta2Argl6~(-1)2C and ~(-1)3C. However, beta2Argl6~(-1)2C underwent 50% less downregulation of receptor expression during beta-agonist exposure compared with the other two haplotypes. Thus these haplotypes direct a potential low-response , phenotype due to decreased steady-state receptor expression combined with wild-type agonist-promoted downregulation (beta2Argl6-11C) and a high-response phenotype due to increased baseline expression combined with decreased agonist-promoted downregulation 2Argl6~(-1)2C). This heterogeneity may contribute to the variability of clinical responses to beta-agonist, and genotyping to identify these 3'-UTR polymorphisms may improve predictive power within the context of beta2-AR haplotypes in pharmacogenetic studies.
机译：首次发布于2007年11月16日; doi：10.1152 / ajplung.00277.2007.-在气道上皮和平滑肌细胞上表达的美元2-肾上腺素能受体（beta2-AR）调节粘膜纤毛清除和松弛，是β-激动剂治疗阻塞性肺疾病的靶标。但是，临床反应显示出广泛的个体间变异性，而无内含子beta2-AR基因的5'侧翼或编码区的遗传变异性不能充分解释这一点。在3个单倍型中发现了最常与支气管扩张剂表型（Argl6）相关的非同义编码多态性，这三个单倍型在3'非翻译区（UTR）多C道中的Cs（11、12或13）数量不同。为了检查这种可变性对受体表达的潜在影响，将BEAS-2B细胞用含有β2-AR（Argl6）编码序列的构建体转染，然后再构建具有各种多态性多C链的3'-UTR。与其他两个单倍型相比，beta2Argl6-HC的mRNA表达降低25％，beta2-AR蛋白表达降低33％。与较低的稳态表达一致，放线菌素D处理后，beta2Argl6-1l 1C mRNA与beta2Argl6〜（-1）2C和〜（-1）3C相比显示出更快，更广泛的降解。然而，与其他两种单倍型相比，β2受体激动剂暴露期间beta2Arg16〜（-1）2C的受体表达下调少50％。因此，这些单倍型指导潜在的低响应表型，这是由于稳态受体表达降低与野生型激动剂促进的下调（beta2Argl6-11C）相结合，而高响应表型则归因于基线表达增加与激动剂促进的降低相结合下调2Arg16〜（-1）2C）。这种异质性可能有助于对β-激动剂的临床反应的变异性，并且在药物遗传学研究中，进行基因分型以鉴定这些3'-UTR多态性可能会改善β2-AR单倍型的预测能力。

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