Trafficking properties of the serotonin receptor variants

项目总结： 5-羟色胺或5-羟色胺(5-羟色胺)是一种内源性递质，与许多 人类行为方式，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，这一单一的递质结合并激活了七个 不同的5-羟色胺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。亲属关系中的变化 由5-羟色胺引起的这些不同信号通路的平衡与一系列综合症有关，包括 抑郁症、抑郁症、双相情感障碍、精神分裂症、强迫症和 注意缺陷多动障碍。选择性5-羟色胺再摄取抑制剂(SSRI)被广泛用于 抑郁症的治疗，在美国超过15%的成年人在 过去12个月。从理论上讲，这些药物的疗效是因为它们能够通过阻断来提高5-羟色胺水平 5-羟色胺再摄取。然而，虽然这些药物在短短2小时内就能提高5-羟色胺水平，但需要4-8周的时间才能 他们在改善抑郁方面变得有效。这表明SSRIs的作用机制是 发射机水平的增加比简单的增加要复杂得多。我们假设高水平的5-羟色胺，产生 通过使用SSRIs，可以及时重新平衡各种5HT受体的表达水平，并通过 所以，提供治疗的好处。具体地说，我们提出，当5HTR被5HTR激活时， 进行内吞和再循环/再敏化，而其他的则被内吞并在溶酶体中降解。 因此，由SSRI提供的高水平的5HTR可以降低某些5HTR亚型的表达， 同时通过其他途径保持高水平的信号--实际上是将5-羟色胺信号转导重新平衡到更多 与非抑郁状态非常相似。在这里，我们将进行全面的分析内吞和 整个5HTR家族的内吞后特性。值得注意的是，关于这方面的知识非常有限 5HTRs的内吞后分选特性。因此，无论结果如何，这些数据都将提供新的 关于SSRIs引起的5-羟色胺水平升高如何改变受体表达的信息，并可能 5-羟色胺治疗的新方法，旨在重新平衡5-羟色胺信号转导。

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.