Physiological Implications of Serotonin Receptor Regulation

描述（由申请人提供）：血清素作为一种丰富的神经递质存在于大脑和全身，在决定许多生物过程中起着重要作用。血清素通过结合和激活神经元和其他细胞表面的G蛋白偶联受体（GPCR）来调节其作用。一种特殊的GPCR，即5 -羟色胺2A受体的活性与几种神经精神疾病有关，几十年来，人们一直在努力调节这种受体的活性，以改善精神疾病的治疗。例如，非典型抗精神病药物氯氮平被设计用来阻断这种受体的活性。其他药物治疗，如选择性5 -羟色胺摄取抑制剂（SSRIs）和相关抗抑郁药，可能通过改变脑5 -羟色胺水平间接影响该受体的活性。5 -羟色胺2A受体也是滥用药物的主要目标，特别是那些被归类为致幻剂的药物；麦角酸二乙基酰胺（LSD）通过直接激活该受体介导其致幻作用。其他间接作用于2A受体的滥用药物有安非他明，尤其是MDMA或“摇头丸”。我们提出了针对5 -羟色胺2A受体调节的药物开发的新基础。我们发现血清素激活2A受体，下游信号是由一种叫做阻滞蛋白的细胞内调节蛋白介导的。体内5 -羟色胺2A受体的调节可能为神经系统对内源性5 -羟色胺水平的敏感性以及对药物的反应性奠定基调。我们的研究探讨了干扰5 -羟色胺2A受体-？体内的相互作用。我们预测破坏血清素2A受体的药物？抑制素的相互作用可能提供了一种方法来改变受体对大脑中血清素水平的敏感性。这些发现可能会激发药物的开发，这些药物可以在消除对内源性血清素过度反应的同时，维持所需的基础血清素能张力。这种药物设计策略可能在临床上对治疗神经精神疾病（包括与药物滥用有关的疾病）有用。公共卫生相关性：我们的研究探讨了扰乱血清素受体调节的生化、生理和行为后果。我们预测，破坏这种调节的药物可能会提供一种改变受体对大脑中血清素水平的敏感性的方法。这些发现可能会激发药物的开发，这些药物可能在临床上对治疗神经精神疾病（如精神分裂症）以及与药物成瘾相关的疾病有用。

DESCRIPTION (provided by applicant): As an abundant neurotransmitter in the brain and throughout the body, serotonin plays a significant role in determining many biological processes. Serotonin mediates its actions by binding to and activating G protein-coupled receptors (GPCR) on the surface of neurons and other cells. The activity of a particular GPCR, the serotonin 2A receptor, is associated with several neuropsychiatric disorders and many efforts spanning several decades have been made to modulate the activity of this receptor to improve psychiatric treatments. For example, the atypical antipsychotic drug clozapine was designed to block the activity of this receptor. Additional pharmaceutical therapeutics, such as selective serotonin uptake inhibitors (SSRIs) and related antidepressants, may indirectly affect activity at this receptor by altering brain serotonin levels. The serotonin 2A receptor is also a prominent target for drugs of abuse, particularly those classified as hallucinogens; lysergic acid diethylamide (LSD) mediates its hallucinogenic effects by directly activating this receptor. Other drugs of abuse that indirectly act at the 2A receptor are amphetamines, particularly MDMA or "ecstacy". We are proposing a new basis for drug development targeting the regulation of the serotonin 2A receptor. We have found that serotonin activates the 2A receptor and downstream signaling is mediated by an intracellular regulatory protein called ?arrestin. Regulation of the serotonin 2A receptor in vivo may set the tone for neurological sensitivity to endogenous levels of serotonin as well as the responsiveness to pharmacological agents. Our studies explore the biochemical, physiological and behavioral consequences of disrupting the serotonin 2A receptor-?arrestin interactions in vivo. We predict that drugs that disrupt the serotonin 2A receptor-?arrestin interaction might provide a means to alter the sensitivity of the receptor to the levels of serotonin present in the brain. These findings may inspire the development of drugs that could maintain a desired basal serotonergic tone while eliminating excessive receptor responsiveness to endogenous serotonin. Such strategies in drug design may prove to be clinically useful for treating neuropsychiatric disorders including those associated with drugs of abuse. PUBLIC HEALTH RELEVANCE: Our studies explore the biochemical, physiological and behavioral consequences of disrupting serotonin receptor regulation. We predict that drugs that disrupt this regulation might provide a means to alter the sensitivity of the receptor to the levels of serotonin present in the brain. These findings may inspire the development of drugs that could be clinically useful for treating neuropsychiatric disorders such as schizophrenia as well as those associated with drug addiction.