Substitution of a mutant alpha(2a)-adrenergic receptor via ''hit and run'' gene targeting reveals the role of this subtype in sedative, analgesic, and anesthetic-sparing responses in vivo
Substitution of a mutant alpha(2a)-adrenergic receptor via ''hit and run'' gene targeting reveals the role of this subtype in sedative, analgesic, and anesthetic-sparing responses in vivo
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DOI：
10.1073/pnas.94.18.9950
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发表时间：
1997-09-02
影响因子：
11.1
通讯作者：
Limbird, LE
中科院分区：
文献类型：
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作者：
Lakhlani, PP;MacMillan, LB;Limbird, LE
去甲肾上腺素在体内具有抗伤害性、镇静和交感神经反应，α(2)肾上腺素能受体(α(2)AR)激动剂可用于临床模拟这些作用。由于缺乏亚型特异性激动剂，无法阐明每个α(2)AR亚型(α(2A)、(α(2B)和α(2C))在这些中枢效应中所起的作用。在这里，我们证明了阿尔法(2)受体激动剂诱导的镇静、麻醉和止痛反应在表达由两步同源重组创建的微妙突变的阿尔法(2A)AR、D79N阿尔法(2A)AR的小鼠系中丢失。伴随着这些功能变化的是D79Nα(2A)AR不能抑制电压钙电流和自发神经元放电(K+电流激活的一种衡量标准)。这些结果提供了确凿的证据，表明α(2A)AR亚型是α(2)AR激动剂临床上重要的中枢作用的主要介体，并提示D79Nα(2A)AR小鼠可以作为探索体内其他可能的α(2A)AR功能的模型。
Norepinephrine contributes to antinociceptive, sedative, and sympatholytic responses in vivo, and alpha(2) adrenergic receptor (alpha(2)AR) agonists are used clinically to mimic these effects. Lack of subtype-specific agonists has prevented elucidation of the role that each alpha(2)AR subtype (alpha(2A), (alpha(2B), and alpha(2C)) plays in these central effects. Here we demonstrate that alpha(2)AR agonist-elicited sedative, anesthetic-sparing, and analgesic responses are lost in a mouse line expressing a subtly mutated alpha(2A)AR, D79N alpha(2A)AR, created by two-step homologous recombination. These functional changes are accompanied by failure of the D79N alpha(2A)AR to inhibit voltagegated Ca2+ currents and spontaneous neuronal firing, a measure of K+ current activation. These results provide definitive evidence that the alpha(2A)AR subtype is the primary mediator of clinically important central actions of alpha(2)AR agonists and suggest that the D79N alpha(2A)AR mouse may serve as a model for exploring other possible alpha(2A)AR functions in vivo.