Therapeutic implications of constitutive activity of receptors: the example of the histamine H3 receptor.
Therapeutic implications of constitutive activity of receptors: the example of the histamine H3 receptor.
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DOI：
10.1007/978-3-7091-6020-6_1
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发表时间：
2003
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影响因子：
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通讯作者：
J. Schwartz;S. Morisset;A. Rouleau;X. Ligneau;F. Gbahou;J. Tardivel-Lacombe;H. Stark;W. Schunack;C. Ganellin;J. Arrang
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文献类型：
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作者：
J. Schwartz;S. Morisset;A. Rouleau;X. Ligneau;F. Gbahou;J. Tardivel-Lacombe;H. Stark;W. Schunack;C. Ganellin;J. Arrang
一些G蛋白偶联受体显示组成性活性，即在不存在激动剂的情况下的自发活性：一部分受体群体采用可以结合和激活G蛋白的构象。虽然这主要是发生在重组或病理突变的受体，该过程的生理相关性仍然存在争议。我们已经解决了这个问题的情况下，组胺H3受体，突触前抑制受体调节组胺释放的大脑。已经确定了一个中性拮抗剂和反向激动剂与可变的内在活性，我们表明，在大脑中的天然H3受体显示高组成活性在体外，在体内，控制内源性组胺的释放。这意味着具有高内在活性的反向激动剂应优选用于在几种精神障碍中作为“认知增强剂”的治疗应用。
Some G-protein-coupled receptors display constitutive activity, that is spontaneous activity in the absence of agonist: a proportion of the receptor population adopts a conformation that can bind and activate G proteins. Whereas this was mainly shown to occur with recombinant or pathologically mutated receptors, the physiological relevance of the process has remained debated. We have adressed this question in the case of the histamine H3receptor, a presynaptic inhibitory receptor regulating histamine release in brain. Having identified a neutral antagonist and inverse agonists with variable intrinsic activity, we show that the native H3receptor in brain displays high constitutive activity in vitro and, in vivo, controls the release of endogenous histamine. This implies that inverse agonists with high intrinsic activity should be preferred for therapeutic application as “cognitive enhancers” in several psychiatric disorders.