Pharmacology of muscarinic receptor subtypes constitutively activated by G proteins
Pharmacology of muscarinic receptor subtypes constitutively activated by G proteins
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DOI：
10.1124/mol.51.2.312
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发表时间：
1997-02-01
影响因子：
3.6
通讯作者：
Brann, MR
中科院分区：
文献类型：
--
作者：
Burstein, ES;Spalding, TA;Brann, MR
我们已经研究了提高G蛋白浓度对一系列激动剂和拮抗剂配体在M1，M3和M5毒蕈碱亚型的药理学的影响，使用功能测定。过表达G（α q）诱导这些受体的组成性活性。组成型活性被测试的每种毒蕈碱拮抗剂完全逆转，这表明它们都是负拮抗剂（反向激动剂）。拮抗剂逆转G蛋白诱导活性和激动剂诱导活性的效力相同，表明作用机制相同。G（α q）的过表达增加了每种测试激动剂的效力和所有部分激动剂的效力。效力的倍数增加与配体效力正相关，最有效的激动剂显示出最大的效力增加。此外，部分激动剂的疗效接近完全激动剂的疗效。受体的组成性活性已被解释为变构模型，其中受体存在于活性和非活性构象之间的自发平衡中，所述活性和非活性构象分别由激动剂和拮抗剂稳定。在这种情况下，药物功效和效力是相互关联的，因为它们都取决于相同的参数，即化合物对活性和非活性状态的受体的绝对和相对亲和力以及活性和非活性状态的受体的比例和浓度。我们所有的数据都与这个模型相一致，即G蛋白水平的提高有利于受体活性构象的形成。根据我们的研究结果，调节G蛋白浓度可能是体内控制受体活性的重要手段。这些结果定义了G蛋白水平和毒蕈碱受体药理学之间的功能关系。
We have examined the effects of raising G protein concentration on the pharmacology of a series of agonist and antagonist ligands at the m1, m3, and m5 muscarinic subtypes using a functional assay. Overexpression of G(alpha q) induced constitutive activity of these receptors. The constitutive activity was reversed completely by every muscarinic antagonist tested, which indicates that they are all negative antagonists (inverse agonists). The potencies of antagonists for reversing G protein-induced activity and agonist-induced activity were identical, suggesting the same mechanism of action. Overexpression of G(alpha q) increased the potencies of every tested agonist and the efficacies of all partial agonists. The fold-gains in potency were positively correlated with ligand efficacy with the most efficacious agonists displaying the greatest potency gains. In addition, the efficacies of partial agonists approached those of full agonists. Constitutive activity of receptors has been explained by allosteric models in which receptors exist in spontaneous equilibrium between active and inactive conformations that are stabilized by agonists and antagonists, respectively. In this context, drug efficacy and potency are interrelated because they both depend on the same parameters, namely the absolute and relative affinities of a compound for receptors in active and inactive states and the ratio and concentrations of receptors in active and inactive states. All of our data are consistent with this model, in which raising G protein levels favors formation of the active conformation of receptors. Based on our findings, regulation of G protein concentration may be an important means of controlling receptor activity in vivo. These results define the functional relationship between G protein levels and muscarinic receptor pharmacology.