Novel actions of inverse agonists on 5-HT2C receptor systems.
Novel actions of inverse agonists on 5-HT2C receptor systems.
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发表时间：
1999-05
影响因子：
3.6
通讯作者：
K. Berg;B. D. Stout;Jodie D. Cropper;S. Maayani;W. Clarke
中科院分区：
文献类型：
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作者：
K. Berg;B. D. Stout;Jodie D. Cropper;S. Maayani;W. Clarke
在配体非依赖性受体活性被优化的细胞系统中（例如当受体过表达或突变时），用反向激动剂的急性治疗降低了基础效应子活性，而长期暴露导致受体系统的敏化和受体上调。然而，很少有研究报道了反向激动剂在非突变受体以相对低密度表达的系统中的作用。在这里，我们研究了反向激动剂在中国仓鼠卵巢细胞中稳定表达的人5-羟色胺（5-HT）2C受体（约250 fmol/mg蛋白质）的作用。在这些细胞中，没有5-HT和5-HT 2C反向激动剂的受体储备没有减少基础磷酸肌醇（IP）的积累，也没有花生四烯酸（AA）的释放，但表现为简单的竞争性拮抗剂，这表明这些受体没有过表达。延长治疗（24小时）与反向激动剂选择性增强5-HT 2C介导的IP积累，但不AA释放。增强作用发生在治疗后4 h内，在3 ~ 4 h内（治疗24 h后）逆转，并可被中性拮抗剂或弱阳性激动剂阻断。增强的反应性不是由于受体上调，但可能涉及G蛋白，Galphaq/11和可能的Galpha 12和Galpha 13的表达的变化。有趣的是，24小时暴露于作用于5-HT 2C受体的反向激动剂也选择性地增强IP积累，但不是AA释放，引起内源性嘌呤能受体的激活。这些数据表明，反相激动剂的作用可能是通过对受体系统的影响介导的，这些受体系统不是这些药物的直接靶点。
In cell systems where ligand-independent receptor activity is optimized (such as when receptors are overexpressed or mutated), acute treatment with inverse agonists reduces basal effector activity whereas prolonged exposure leads to sensitization of receptor systems and receptor up-regulation. Few studies, however, have reported effects of inverse agonists in systems where nonmutated receptors are expressed at relatively low density. Here, we investigated the effects of inverse agonists at human serotonin (5-HT)2C receptors expressed stably in Chinese hamster ovary cells ( approximately 250 fmol/mg protein). In these cells, there is no receptor reserve for 5-HT and 5-HT2C inverse agonists did not reduce basal inositol phosphate (IP) accumulation nor arachidonic acid (AA) release but behaved as simple competitive antagonists, suggesting that these receptors are not overexpressed. Prolonged treatment (24 h) with inverse agonists enhanced selectively 5-HT2C-mediated IP accumulation but not AA release. The enhancing effect occurred within 4 h of treatment, reversed within 3 to 4 h (after 24-h treatment), and could be blocked with neutral antagonists or weak positive agonists. The enhanced responsiveness was not due to receptor up-regulation but may involve changes in the expression of the G protein, Galphaq/11 and possibly Galpha12 and Galpha13. Interestingly, 24-h exposure to inverse agonists acting at 5-HT2C receptors also selectively enhanced IP accumulation, but not AA release, elicited by activation of endogenous purinergic receptors. These data suggest that actions of inverse agonists may be mediated through effects on receptor systems that are not direct targets for these drugs.