Mechanisms of 5HT2A Receptor Desensitization

5HT2A受体脱敏机制

• 批准号: 6916264
• 负责人: Nancy A Muma
• 金额: $ 23.68万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6916264
• 关键词: G protein; SDS polyacrylamide gel electrophoresis; autoradiography; biological signal transduction; guanosinetriphosphatase activating protein; immunocytochemistry; immunoprecipitation; inhibitor /antagonist; laboratory rat; northern blottings; phosphorylation; protein structure function; radioimmunoassay; receptor sensitivity; serotonin receptor; stimulant /agonist; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): The long-term goals of our studies are to identify the molecular mechanisms of desensitization of serotonin 2A (5-HT2A) receptor signaling. Adaptive changes in post-synaptic 5-HT2A receptor signaling underlie the mechanism of action of several drug treatments for psychiatric disorders including anxiety, schizophrenia, depression, and bipolar disorder. Paradoxically, chronic treatment with both 5-HT2A receptor agonist such as DOI and antagonists including olanzapine desensitize 5-HT2a receptor signaling. Atypical antipsychotics are 5-HT2A receptor antagonists. Although these drugs are widely used, significant numbers of individuals are refractory to drug therapy and their effectiveness is delayed about 2 weeks after treatment is initiated. To help to resolve these problems, we plan to investigate the mechanisms by which 5-HT2A receptor signaling is desensitized. We will examine the mechanisms of desensitization of 5-HT2A receptor signaling induced with 5-HT2A receptor agonists (Aim 1), 5-HT2a receptor antagonists (Aim 2) and regulators of G protein signaling (RGS) proteins (Aim 3) in cells in culture and in vivo. Our hypothesis is that Jak/Stat signaling is critical for antagonist-induced desensitization, while the receptor-G protein functioning is reduced in agonist-induced desensitization of 5-HT2.A receptor signaling. We will test the hypothesis that RGS proteins also cause adaptive changes leading to 5-HT2A receptor desensitization via mechanisms in addition to acting as GTPase-activating proteins (GAPs). Neuroendocrine responses to 5-HT2A receptor-stimulation will be used as an index of desensitization of 5-HT2A receptor signaling in vivo. A major advantage of the neuroendocrine challenge tests is that the results obtained in experimental animals can be rapidly applied to humans since these tests can be performed in humans. Ultimately the purpose of these studies is to identify new targets for therapeutic intervention for psychiatric disorders currently treated with drugs that alter 5-HT2A receptor signaling. By understanding the mechanisms involved in neuroadaptation, new approaches can be developed to reduce the delay in therapeutic response and treat individuals refractory to current therapies

描述（由申请人提供）：我们研究的长期目标是确定血清素 2A (5-HT2A) 受体信号转导脱敏的分子机制。突触后 5-HT2A 受体信号传导的适应性变化是多种精神疾病药物治疗的作用机制的基础，这些精神疾病包括焦虑症、精神分裂症、抑郁症和双相情感障碍。矛盾的是，长期使用 5-HT2A 受体激动剂（例如 DOI）和拮抗剂（包括奥氮平）治疗会使 5-HT2a 受体信号传导脱敏。非典型抗精神病药是 5-HT2A 受体拮抗剂。尽管这些药物被广泛使用，但仍有相当多的人对药物治疗产生耐药性，并且其有效性会在治疗开始后约 2 周延迟。为了帮助解决这些问题，我们计划研究 5-HT2A 受体信号传导脱敏的机制。我们将研究细胞中 5-HT2A 受体激动剂（目标 1）、5-HT2a 受体拮抗剂（目标 2）和 G 蛋白信号（RGS）蛋白调节剂（目标 3）诱导的 5-HT2A 受体信号脱敏机制在培养和体内。我们的假设是，Jak/Stat 信号传导对于拮抗剂诱导的脱敏至关重要，而受体 G 蛋白功能在激动剂诱导的 5-HT2.A 受体信号传导脱敏中降低。我们将测试以下假设：除了充当 GTP 酶激活蛋白 (GAP) 之外，RGS 蛋白还通过其他机制引起适应性变化，从而导致 5-HT2A 受体脱敏。对5-HT2A受体刺激的神经内分泌反应将被用作体内5-HT2A受体信号转导脱敏的指标。神经内分泌挑战测试的一个主要优点是，在实验动物中获得的结果可以快速应用于人类，因为这些测试可以在人类身上进行。这些研究的最终目的是确定目前使用改变 5-HT2A 受体信号传导药物治疗的精神疾病的治疗干预新靶点。通过了解神经适应所涉及的机制，可以开发新方法来减少治疗反应的延迟并治疗对当前疗法难治的个体