Genetic Dissection of α2-Adrenoceptor Functions in Adrenergic versus Nonadrenergic Cells
Genetic Dissection of α2-Adrenoceptor Functions in Adrenergic versus Nonadrenergic Cells
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DOI：
10.1124/mol.109.054544
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发表时间：
2009-05-01
影响因子：
3.6
通讯作者：
Hein, Lutz
中科院分区：
文献类型：
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作者：
Gilsbach, Ralf;Roeser, Christoph;Hein, Lutz
Eα(2)-肾上腺素受体介导交感系统的不同功能，是治疗心血管疾病、抑郁、疼痛、青光眼和阿片类药物戒断期间交感神经激活的靶点。为了确定肾上腺素能神经元上的α(2)受体或非肾上腺素能神经元上的α(2)受体是否介导了α(2)激动剂的生理和药理反应，我们使用多巴胺β-羟基酶(DBH)启动子来驱动α(2A)受体在去甲肾上腺素能和肾上腺素能细胞中的表达。将DBH-α(2A)转基因小鼠与缺乏α(2A)和α(2C)受体的双基因敲除小鼠杂交，获得肾上腺素能细胞选择性表达α(2)A受体的品系。这些小鼠接受了全面的表型分析，并与野生型小鼠进行了比较，野生型小鼠在肾上腺素能和非肾上腺素能细胞中都表达α(2A)和α(2C)受体，而α(2A)/α(2C)双基因敲除小鼠在任何细胞类型中都不表达这些受体。我们惊讶地发现，只有少数以前归因于α(2A)-肾上腺素受体的功能是由肾上腺素能神经元上的受体介导的，包括反馈抑制交感神经释放去甲肾上腺素和自发运动活动。其他的激动剂效应，包括止痛、低温、镇静和省去麻醉剂，都是由非肾上腺素能细胞中的α(2)受体介导的。在缺乏去甲肾上腺素的多巴胺β-羟基酶基因敲除小鼠中，α(2)激动剂美托咪定仍然导致翻正反射的丧失，证实刺激α(2)肾上腺素受体的镇静作用不是通过自身受体介导的对去甲肾上腺素释放的抑制来实现的。这项研究为修订目前关于α(2)-肾上腺素能受体的观点铺平了道路，并为未来的药物开发提供了重要的新考虑。
e alpha(2)-Adrenoceptors mediate diverse functions of the sympathetic system and are targets for the treatment of cardiovascular disease, depression, pain, glaucoma, and sympathetic activation during opioid withdrawal. To determine whether alpha(2)-adrenoceptors on adrenergic neurons or alpha(2)-adrenoceptors on nonadrenergic neurons mediate the physiological and pharmacological responses of alpha(2)-agonists, we used the dopamine beta-hydroxylase (Dbh) promoter to drive expression of alpha(2A)-adrenoceptors exclusively in noradrenergic and adrenergic cells of transgenic mice. Dbh-alpha(2A) transgenic mice were crossed with double knockout mice lacking both alpha(2A)- and alpha(2C)-receptors to generate lines with selective expression of alpha(2)A-autoreceptors in adrenergic cells. These mice were subjected to a comprehensive phenotype analysis and compared with wild-type mice, which express alpha(2A)- and alpha(2C)-receptors in both adrenergic and nonadrenergic cells, and alpha(2A)/alpha(2C) double-knockout mice, which do not express these receptors in any cell type. We were surprised to find that only a few functions previously ascribed to alpha(2A)-adrenoceptors were mediated by receptors on adrenergic neurons, including feedback inhibition of norepinephrine release from sympathetic nerves and spontaneous locomotor activity. Other agonist effects, including analgesia, hypothermia, sedation, and anesthetic-sparing, were mediated by alpha(2)-receptors in nonadrenergic cells. In dopamine beta-hydroxylase knockout mice lacking norepinephrine, the alpha(2)-agonist medetomidine still induced a loss of the righting reflex, confirming that the sedative effect of alpha(2)-adrenoceptor stimulation is not mediated via autoreceptor-mediated inhibition of norepinephrine release. The present study paves the way for a revision of the current view of the alpha(2)-adrenergic receptors, and it provides important new considerations for future drug development.