Mechanisms of 5HT2A Receptor Desensitization

描述（由申请人提供）：我们研究的长期目标是确定5-羟色胺2A （5-HT2A）受体信号脱敏的分子机制。突触后5-HT2A受体信号的适应性变化是几种药物治疗精神疾病的作用机制的基础，包括焦虑、精神分裂症、抑郁症和双相情感障碍。矛盾的是，使用DOI等5-HT2A受体激动剂和奥氮平等拮抗剂进行慢性治疗会使5-HT2A受体信号脱敏。非典型抗精神病药物是5-HT2A受体拮抗剂，尽管这些药物被广泛使用，但相当数量的个体对药物治疗难治。为了帮助解决这一矛盾并确定调节5-HT2A受体信号传导的新靶点，我们计划研究5-HT2A受体信号脱敏的机制。我们将研究5-HT2A受体激动剂（Aim 1）和5-HT2A受体拮抗剂（Aim 2）在培养和体内细胞中诱导5-HT2A受体信号脱敏的机制。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，导致5-HT2A受体信号的适应性变化。我们将基于我们的初步发现，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受体拮抗剂通过增加JAK/STAT信号（STAT是一种转录因子）来增加RGS7蛋白的表达。除了现代分子生物学方法外，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受体信号脱敏的指标。神经内分泌激发试验的一个主要优点是，在实验动物中获得的结果可以迅速应用于人类，因为这些试验可以在人类中进行。这些研究的最终目的是为目前使用改变5-HT2A受体信号的药物治疗的精神疾病确定新的治疗干预靶点。通过了解信号传导和神经适应的机制，可以开发新的方法来减少抗精神病药和抗抑郁药治疗反应的延迟，并治疗对当前治疗难治性的个体。公共卫生相关性：突触后5HT2A/2C受体信号的适应性变化可能是几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，如奥氮平，可使5- ht2a和5- ht2c受体脱敏，而5-HT摄取阻滞剂可改变5- ht2a受体信号传导的功效。然而，5-HT2A受体信号传导中这些适应性变化的分子机制尚不清楚。本提案的目的是确定5-HT2A受体激动剂和拮抗剂的适应性反应机制。通过发现5-HT2A受体信号转导和脱敏的分子机制，将确定新的治疗干预靶点。

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.