Mechanisms of 5HT2A Receptor Desensitization

5HT2A受体脱敏机制

基本信息

批准号：
7462079
负责人：
Nancy A Muma
金额：
$ 32.36万
依托单位：
UNIVERSITY OF KANSAS LAWRENCE
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-07-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7462079
关键词：
ADRBK1 gene Agonist Animals Antidepressive Agents Antipsychotic Agents Anxiety Binding Bipolar Disorder Boxing Brain Calcium Calmodulin Cell Line Cells Chronic Cultured Cells Data Disease Dose Enzymes Figs - dietary Fluoxetine Funding GTP-Binding Proteins Gene Expression Genetic Transcription Goals Grant Gray unit of radiation dose HTR2A gene Human Individual Janus kinase Lead Mediating Mental Depression Mental disorders Modeling Modification Molecular Molecular Biology Monomeric GTP-Binding Proteins Neurosecretory Systems Nuclear Numbers Pathway interactions Pharmaceutical Preparations Pharmacotherapy Phosphatidylinositol 4,5-Diphosphate Phosphorylation Phosphotransferases Post-Translational Protein Processing Protein Kinase C Proteins Public Health Purpose RGS Proteins Rattus Receptor Signaling Refractory STAT protein Schizophrenia Second Messenger Systems Serotonin Serotonin Receptor 5-HT2A Serotonin Receptor 5-HT2C Signal Pathway Signal Transduction Signal Transduction Pathway Signaling Protein Synapses System Testing Therapeutic Therapeutic Intervention Transglutaminases Translations atypical antipsychotic base crosslink desensitization in vivo indexing neuroadaptation neuropsychiatry novel novel strategies olanzapine protein expression receptor research study response second messenger transcription factor transglutaminase 1 uptake

项目摘要

DESCRIPTION (provided by applicant): The long-term goal of our studies is 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 agonists such as DOI and antagonists including olanzapine desensitize 5-HT2A receptor signaling. Atypical antipsychotics are 5-HT2A receptor antagonists, and although these drugs are widely used, significant numbers of individuals are refractory to drug therapy. To help to resolve this paradox and identify novel targets that regulate 5-HT2A receptor signaling, 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), and 5-HT2A receptor antagonists (Aim 2) in cells in culture and in vivo. Our central hypothesis is that agonists induce post-translation modifications while antagonists induce transcriptional changes to cause adaptational changes in 5-HT2A receptor signaling. We will build on our preliminary findings that 5-HT2A receptor agonists induce post- translational modifications to G proteins while chronic treatment with a 5-HT2A receptor antagonist increases RGS7 protein expression via increases in JAK/STAT signaling (STAT being a transcription factor). In addition to modern molecular biology approaches, we use neuroendocrine responses to 5-HT2A receptor-stimulation 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 signaling and neuroadaptation, new approaches can be developed to reduce the delay in therapeutic response with antipsychotic and antidepressant therapies and treat individuals refractory to current therapies. PUBLIC HEALTH RELEVANCE: Adaptive changes in post-synaptic 5HT2A/2C receptor signaling may underlie the mechanism of action of several drug treatments for neuropsychiatric. For example, several antipsychotic drugs, such as olanzapine, desensitize both 5-HT2A and 5-HT2C receptors while 5- HT uptake blockers alter the efficacy of 5-HT2A receptor signaling. However, the molecular mechanisms that underlie these adaptive changes in 5-HT2A receptor signaling are not well understood. The purpose of this proposal is to determine the mechanisms involved in the adaptational responses to 5-HT2A receptor agonists and antagonists. By discovering the molecular mechanisms underlying signaling and desensitization of 5-HT2A receptor signaling, new targets for therapeutic intervention will be identified.

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耐药。为了帮助解决这一悖论并确定调节 5-HT2A 受体信号传导的新靶点，我们计划研究 5-HT2A 受体信号传导脱敏的机制。我们将研究培养细胞和体内细胞中 5-HT2A 受体激动剂（目标 1）和 5-HT2A 受体拮抗剂（目标 2）诱导的 5-HT2A 受体信号转导脱敏机制。我们的中心假设是激动剂诱导翻译后修饰，而拮抗剂诱导转录变化，从而引起 5-HT2A 受体信号传导的适应性变化。我们将基于我们的初步发现，即 5-HT2A 受体激动剂诱导 G 蛋白的翻译后修饰，而长期使用 5-HT2A 受体拮抗剂治疗可通过增加 JAK/STAT 信号传导（STAT 是转录因子）来增加 RGS7 蛋白表达。除了现代分子生物学方法之外，我们还使用对 5-HT2A 受体刺激的神经内分泌反应作为体内 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。通过了解信号传导和神经适应所涉及的机制，可以开发新方法来减少抗精神病药物和抗抑郁药物治疗反应的延迟，并治疗对当前治疗无效的个体。公共卫生相关性：突触后 5HT2A/2C 受体信号传导的适应性变化可能是多种神经精神药物治疗的作用机制的基础。例如，一些抗精神病药物，例如奥氮平，使 5-HT2A 和 5-HT2C 受体脱敏，而 5-HT 摄取阻滞剂则改变 5-HT2A 受体信号传导的功效。然而，5-HT2A 受体信号传导这些适应性变化背后的分子机制尚不清楚。本提案的目的是确定对 5-HT2A 受体激动剂和拮抗剂的适应性反应所涉及的机制。通过发现 5-HT2A 受体信号传导和脱敏的分子机制，将确定治疗干预的新靶点。