PHYSIOLOGICAL-EFFECTS OF INVERSE AGONISTS IN TRANSGENIC MICE WITH MYOCARDIAL OVEREXPRESSION OF THE BETA(2)-ADRENOCEPTOR
PHYSIOLOGICAL-EFFECTS OF INVERSE AGONISTS IN TRANSGENIC MICE WITH MYOCARDIAL OVEREXPRESSION OF THE BETA(2)-ADRENOCEPTOR
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DOI：
10.1038/374272a0
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发表时间：
1995-03-16
期刊：
影响因子：
64.8
通讯作者：
LEFKOWITZ, RJ
中科院分区：
文献类型：
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作者：
BOND, RA;LEFF, P;LEFKOWITZ, RJ
G蛋白偶联受体被认为具有一种无活性的构象（R），需要激动剂诱导的构象变化才能实现受体/G蛋白偶联（1 - 3）。但是新的证据表明存在一种二态模型（4 - 19），在该模型中，受体在无活性构象（R）和一种在无配体存在时可与G蛋白偶联的自发活性构象（R*）之间处于平衡状态（图1）。经典激动剂对R*具有高亲和力并增加R*的浓度，而反向激动剂对R具有高亲和力并降低R*的浓度。中性竞争性拮抗剂对R和R*具有相等的亲和力，不会改变平衡，但可以竞争性拮抗激动剂和反向激动剂的作用。由于缺乏合适的体内模型系统，反向激动剂存在的证据局限于计算机模拟（7，8）和体外系统（5，9 - 12，20 - 23）。我们使用了一种转基因小鼠模型，其中β₂ - 肾上腺素能受体在心肌中过度表达非常显著，以至于存在大量自发激活的受体（R*），在无激动剂的情况下诱导出最大反应（24）。我们表明β₂ - 肾上腺素能受体配体ICI - 118,551起到反向激动剂的作用，为反向激动剂的存在提供了证据，并验证了G蛋白偶联受体激活的二态模型。
G-PROTEIN-COUPLED receptors are thought to have an inactive conformation (R), requiring an agonist-induced conformational change for receptor/G-protein coupling(1-3). But new evidence suggests a two-state model(4-19) in which receptors are in equilibrium between the inactive conformation (R), and a spontaneously active conformation (R*) that can couple to G protein in the absence of ligand (Fig, 1). Classic agonists have a high affinity for R* and increase the concentration of R*, whereas inverse agonists have a high affinity for R and decrease the concentration of R*. Neutral competitive antagonists have equal affinity for R and R* and do not displace the equilibrium, but can competitively antagonize the effects both of agonists and of inverse agonists. The lack of suitable in vivo model systems has restricted the evidence for the existence of inverse agonists to computer simulations(7,8) and in vitro systems(5,9-12,20-23). We have used a transgenic mouse model in which there is such marked myocardial overexpression of beta(2)-adrenoceptors that a significant population of spontaneously activated receptor (R*) is present, inducing a maximal response without agonist(24). We show that the beta(2)-adrenoceptor ligand ICI-118,551 functions as an inverse agonist, providing evidence supporting the existence of inverse agonists and validating the two-state model of G-protein-coupled receptor activation.