Rapid desensitization of the serotonin(2C) receptor system: effector pathway and agonist dependence.
Rapid desensitization of the serotonin(2C) receptor system: effector pathway and agonist dependence.
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DOI：
10.1124/jpet.302.3.957
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发表时间：
2002-09
期刊：
影响因子：
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通讯作者：
B. D. Stout;W. Clarke;K. Berg
中科院分区：
文献类型：
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作者：
B. D. Stout;W. Clarke;K. Berg
5-羟色胺（2C）（5-HT（2C））受体与多种效应机制偶联，包括磷脂酶A（2）介导的花生四烯酸（AA）释放和磷脂酶C介导的肌醇磷酸（IP）产生。激动剂的相对功效取决于测量哪种反应（AA释放或IP积累）而不同。在这项研究中，我们研究了5-HT（2C）受体介导的AA释放和IP积累的快速脱敏的特性和激动剂依赖性，同时从相同的细胞群体测量。用5-HT预处理使最大浓度的5-HT引起AA释放和IP累积的能力降低约60%;然而，AA反应的脱敏（t（1/2）= 1.3 min）比IP反应（t（1/2）= 6.9 min）更快。此外，IP反应的脱敏比AA反应更敏感（发生在较低的受体占有水平）。此外，在响应于次最大5-HT浓度，在初始瞬时脱敏后，AA响应增强高达约250%。最大脱敏后，两种反应均恢复，但AA反应的恢复是完全的，比IP更快。两种反应的脱敏也是激动剂依赖性的，并且激动剂引起脱敏的能力与其激活信号传导的功效无关。这些数据表明，5-HT（2C）受体系统的脱敏是激动剂和效应途径依赖性的，并强调需要研究多种细胞对多种激动剂的反应，以了解受体介导的信号系统。
The serotonin(2C) (5-HT(2C)) receptor couples to multiple effector mechanisms, including phospholipase A(2)-mediated arachidonic acid (AA) release and phospholipase C-mediated production of inositol phosphates (IP). Agonist relative efficacy differs depending upon which response (AA release or IP accumulation) is measured. In this study, we investigated the characteristics and agonist dependence of rapid desensitization of 5-HT(2C) receptor-mediated AA release and IP accumulation measured simultaneously from the same cell population. Pretreatment with 5-HT reduced the ability of a maximal concentration of 5-HT to elicit AA release and IP accumulation by about 60%; however, the AA response desensitized more rapidly (t(1/2) = 1.3 min) than the IP response (t(1/2) = 6.9 min). In addition, desensitization of the IP response was more sensitive (occurred at lower receptor occupancy levels) than the AA response. Moreover, in response to submaximal 5-HT concentrations, after an initial transient desensitization, the AA response was enhanced by up to approximately 250%. After maximal desensitization, both responses recovered, but recovery of the AA response was complete and faster than that for IP. Desensitization of both responses was also agonist-dependent, and the capacity of agonists to elicit desensitization was not related to their efficacy to activate signaling. These data suggest that desensitization of the 5-HT(2C) receptor system is both agonist- and effector pathway-dependent and underscore the need to study multiple cellular responses to multiple agonists to understand receptor-mediated signaling systems.