Trafficking properties of the serotonin receptor variants

项目概要： 5-羟色胺或5-羟色胺（5 HT）是一种内源性递质，广泛涉及许多疾病， 人的行为模式，包括情绪，性欲，食欲和睡眠，以及血小板的外周功能 聚集、免疫反应和骨密度。在大脑中，这个单一的递质结合并激活了七个 不同的5 HT受体家族，具有五种不同的信号转导模式，包括所有四类G 蛋白偶联受体（GPCR）（Gi、Gs、Gq和G12/13）和配体门控离子通道。相对人的改变 5 HT对这些不同信号通路的平衡已经涉及到多种综合征，包括 抑郁症、重度抑郁症、双相情感障碍、精神分裂症、强迫症和 注意力缺陷多动障碍选择性5-羟色胺再摄取抑制剂（SSRIs）被广泛用于 治疗抑郁症，超过15%的美国成年人在治疗期间服用抗抑郁药。 过去12个月理论上，这些药物的疗效是由于它们能够通过阻断5 HT而增加5 HT水平。 再摄取5 HT。然而，虽然这些药物在短短2小时内增加5 HT水平，但需要4-8周才能达到。 使其有效改善抑郁症。这表明SSRIs的作用机制是 比简单地增加发射器电平更复杂。我们假设，高水平的5-HT，产生 通过使用SSRIs，可以及时重新平衡各种5 HT受体的表达水平， 从而提供治疗益处。具体地说，我们提出，当被5 HT激活时， 经历内吞作用和再循环/再敏化，而其它的在溶酶体中被内吞和降解。 由SSRI提供的高水平的5-HT因此可以降低某些亚型的5-HTR的表达， 同时通过其他途径维持高水平的信号传导--实际上“重新平衡”了5 HT信号传导， 与非抑郁状态非常相似。在这里，我们将进行一个全面的分析， 整个5 HTR家族的内吞后性质。值得注意的是，关于 5 HTR的内吞后分选特性。因此，无论结果如何，这些数据将提供新的 关于SSRIs导致的5-HT水平升高如何改变受体表达的信息， 旨在重新平衡5-HT信号转导的5-羟色胺治疗新方法。

Project summary: Serotonin, or 5 hydroxytryptamine (5HT) is an endogenous transmitter that is broadly implicated in many modalities of human behavior including mood, libido, appetite and sleep, as well as peripheral functions in platelet aggregation, immune response and bone density. In the brain, this single transmitter binds and activates seven different families of 5HT receptors with five distinct modes of signal transduction, including all four classes of G protein-coupled receptor (GPCR) (Gi, Gs, Gq and G12/13) and a ligand-gated ion channel. Alterations in the relative balance of these diverse signaling pathways by 5HT has been implicated in a plethora of syndromes including depression, major depressive disorder, bipolar disorder, schizophrenia, obsessive compulsive disorder and attention deficit hyperactivity disorder. Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed for the treatment of depression, and more than 15% of adults in the US have taken an antidepressant within the past 12 months. In theory, the efficacy of these drugs is due to their ability to increase 5HT levels by blocking reuptake of 5HT. However, while these drugs increase 5HT levels in as little as 2 hours, it takes 4-8 weeks for them to become effective at ameliorating depression. This suggests that the mechanism of action of SSRIs is more complicated than simple increases in transmitter levels. We hypothesize that high levels of 5HT, produced through use of SSRIs, can, in time, rebalance the expression levels of the various 5HT receptors and, by doing so, provide therapeutic benefit. Specifically, we propose that some of the 5HTRs, when activated by 5HT, undergo endocytosis and recycling/resensitization while others are endocytosed and degraded in the lysosome. The high levels of 5HT provided by the SSRI can, thereby, drive down expression of certain subtypes of 5HTR, while maintaining a high level of signaling through others--in effect “rebalancing” 5HT signal transduction to more closely resemble the non-depressed state. Here, we will perform a comprehensive analysis of the endocytic and post-endocytic properties of the entire family of 5HTRs. Remarkably, there is very limited knowledge regarding the post-endocytic sorting properties of the 5HTRs. Hence, regardless of outcome, these data will provide new information regarding how increased 5HT levels, due to SSRIs, could alter receptor expression and could inform new approaches to serotonin therapeutics designed to rebalance 5HT signal transduction.