Effector pathway-dependent relative efficacy at serotonin type 2A and 2C receptors: Evidence for agonist-directed trafficking of receptor stimulus
Effector pathway-dependent relative efficacy at serotonin type 2A and 2C receptors: Evidence for agonist-directed trafficking of receptor stimulus
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DOI：
10.1124/mol.54.1.94
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发表时间：
1998-07-01
影响因子：
3.6
通讯作者：
Clarke, WP
中科院分区：
文献类型：
--
作者：
Berg, KA;Maayani, S;Clarke, WP
有许多实例表明，单个受体直接偶联到一个以上的细胞信号转导途径。虽然传统的受体理论允许激动剂激活多种细胞效应物，但它预测激动剂激活每个效应物途径的相对程度（相对功效）必须相同。在当前的实验中，我们证明了人5-羟色胺（5-HT 2A）和5-MT 2C受体的激动剂不同地激活两种独立地与受体偶联的信号转导途径[磷脂酶C（PLC）介导的磷酸肌醇（IP）积累和磷脂酶A（2）（PLA（2））介导的花生四烯酸（AA）释放]。激动剂的相对效力根据测量的信号转导途径而不同。此外，相对于5-HT，一些5-HT 2C激动剂（例如，3-三氟甲基苯基-哌嗪）优先激活PLC-IP途径，而其他（例如，麦角酸二乙基酰胺）有利于PLA（2）-AA途径。相比之下，当测量两种依赖性反应（IP蓄积和钙动员）时，激动剂的相对功效没有差异。这些数据强烈支持Kenakin最近提出的称为“受体刺激物的激动剂定向运输”的假设[Trends Pharmacol Sci 16：232-238（1995）]。5-HT 2C激动剂的浓度-反应曲线与受体激活的三态模型拟合良好，表明两种活性受体状态可能足以解释途径依赖性激动剂的疗效。在一组受体选择性药物中优化优先效应子活性的合理药物设计有望提高临床有用药物的选择性。
There are many examples of a single receptor coupling directly to more than one cellular signal transduction pathway. Although traditional receptor theory allows for activation of multiple cellular effecters by agonists, it predicts that the relative degree of activation of each effector pathway by an agonist (relative efficacy) must be the same. In the current experiments, we demonstrate that agonists at the human serotonin, (5-HT2A)and 5-MT2C receptors activate differentially two signal transduction pathways independently coupled to the receptors [phospholipase C (PLC)-mediated inositol phosphate (IP) accumulation and phospholipase A(2) (PLA(2))-mediated arachidonic acid (AA) release]. The relative efficacies of agonists differed depending on which signal transduction pathway was measured. Moreover, relative to 5-HT, some 5-HT2C agonists (e.g., 3-trifluoromethylphenyl-piperazine) preferentially activated the PLC-IP pathway, whereas others (e.g., lysergic acid diethylamide) favored the PLA(2)-AA pathway. In contrast, when two dependent responses were measured (IP accumulation and calcium mobilization), agonist relative efficacies were not different. These data strongly support the hypothesis termed "agonist-directed trafficking of receptor stimulus" recently proposed by Kenakin [Trends Pharmacol Sci 16:232-238 (1995)]. Concentration-response curves to 5-HT2C agonists were fit well by a three-state model of receptor activation, suggesting that two active receptor states may be sufficient to explain pathway-dependent agonist efficacy. Rational drug design that optimizes preferential effector activity within a group of receptor-selective drugs holds the promise of increased selectivity in clinically useful agents.