Selectivity of Agonists for the Active State of M1 to M4 Muscarinic Receptor Subtypes
Selectivity of Agonists for the Active State of M1 to M4 Muscarinic Receptor Subtypes
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DOI：
10.1124/jpet.108.145219
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发表时间：
2009-01-01
影响因子：
3.5
通讯作者：
Ehlert, Frederick J.
中科院分区：
文献类型：
--
作者：
Figueroa, Katherine W.;Griffin, Michael T.;Ehlert, Frederick J.
我们测量了毒蕈碱激动剂的内在相对活性（RA(i)），以检测受体亚型和信号通路的可能选择性。RA(i)是相对于标准激动剂表达的GPCR活性状态的激动剂的微观亲和力常数的相对度量。首先，我们估计了一组作用于M-4毒蕈碱受体的激动剂的RA(i)值，这些激动剂与三种不同的G蛋白途径偶联：G(i)抑制cAMP积累，G(s)刺激cAMP积累，G α(15)刺激磷酸肌苷水解。我们的结果显示，每种激动剂的RA(i)值相似，表明m4受体的相同活性状态触发了三种G蛋白的激活。我们还估计了在中国仓鼠卵巢细胞中稳定转染的M-1到M-4毒蕈碱亚型激动剂的RA(i)值。结果表明，McN-A-343 [4-I-[3-氯苯基]氨甲酰氧基)-2-丁基三甲基氯铵]对M-1和M-4亚型具有选择性，匹罗卡平对M-1和M-3亚型具有选择性。其他激动剂在M-1到M-4受体之间缺乏明显的选择性。最后，我们从已发表的关于M-1、M-2和M-3毒蕈碱反应的文献中估计RA(i)值，得到与我们自己研究一致的结果。我们的结果表明，RA(i)估计是一种有用的受体依赖的激动剂活性测量。
We measured the intrinsic relative activity (RA(i)) of muscarinic agonists to detect possible selectivity for receptor subtypes and signaling pathways. RA(i) is a relative measure of the microscopic affinity constant of an agonist for the active state of a GPCR expressed relative to that of a standard agonist. First, we estimated RA(i) values for a panel of agonists acting at the M-4 muscarinic receptor coupled to three distinct G-protein pathways: G(i) inhibition of cAMP accumulation, G(s) stimulation of cAMP accumulation, and G alpha(15) stimulation of phosphoinositide hydrolysis. Our results show similar RA(i) values for each agonist, suggesting that the same active state of the M 4 receptor triggers the activation of the three G proteins. We also estimated RA(i) values for agonists across M-1 to M-4 muscarinic subtypes stably transfected in Chinese hamster ovary cells. Our results show selectivity of McN-A-343 [4-I-[3-chlorophenyl]carbamoyloxy)-2- butynyltrimethylammnonium chloride] for the M-1 and M-4 subtypes and selectivity of pilocarpine for the M-1 and M-3 subtypes. The other agonists tested lacked marked selectivity among M-1 to M-4 receptors. Finally, we estimated RA(i) values from published literature on M-1, M-2, and M-3 muscarinic responses and obtained results consistent with our own studies. Our results show that the RA(i) estimate is a useful receptor-dependent measure of agonist activity.