Trafficking properties of the serotonin receptor variants

血清素受体变体的贩运特性

• 批准号: 10742437
• 负责人: JENNIFER L WHISTLER
• 金额: $ 23.05万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10742437
• 关键词: Acute; Adult; Affinity; Agonist; Antidepressive Agents; Attention; Attention deficit hyperactivity disorder; Behavior; Binding; Bipolar Depression; Bipolar Disorder; Bone Density; Brain; Calcium; Cell membrane; Cells; Central Nervous System Diseases; Clinical Medicine; Coupled; Cytoplasmic Tail; Data; Degradation Pathway; Desire for food; Disease; Drug Targeting; Drug usage; Early Endosome; Endocytosis; Equilibrium; Event; Family; G-Protein-Coupled Receptors; GTP-Binding Proteins; Genes; Genetic Variation; Goals; Hallucinogens; Hour; Human; Immune response; Intervention; Ion Channel Gating; Knock-out; Knowledge; Libido; Ligands; Link; Lysosomes; Major Depressive Disorder; Mediating; Mental Depression; Modality; Moods; Neurons; Obsessive-Compulsive Disorder; Outcome; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Pharmacologic Substance; Platelet aggregation; Property; Protein Sortings; RNA Splicing; Receptor Signaling; Recycling; Schizophrenia; Selective Serotonin Reuptake Inhibitor; Serotonergic System; Serotonin; Signal Pathway; Signal Transduction; Signaling Protein; Sleep; Sorting; Syndrome; Testing; Therapeutic; Time; Treatment Efficacy; Variant; autism spectrum disorder; desensitization; design; drug efficacy; experimental study; genetic variant; member; novel strategies; pharmacologic; receptor; receptor expression; receptor recycling; reduce symptoms; response; reuptake; segregation; serotonin receptor; theories; trafficking; triptans

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.

项目摘要： 5-羟色胺或5个羟色胺（5HT）是一种内源性发射器，广泛涉及许多 人类行为的方式，包括情绪，性欲，食欲和睡眠，以及血小板中的周围功能 聚集，免疫响应和骨密度。在大脑中，该单个发射器结合并激活七个 5HT接收器的不同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。相对的改变 在众多综合症中隐含了这些潜水员信号通路的平衡 抑郁症，重度抑郁症，躁郁症，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）被广泛规定 抑郁症的治疗以及美国超过15％的成年人在 过去12个月。从理论上讲，这些药物的效率是由于它们通过阻止增加5HT水平的能力 5ht的重新摄取。但是，尽管这些药物在2小时内提高了5HT水平，但需要4-8周 他们可以有效地改善抑郁症。这表明SSRI的作用机理是 比简单的发射机水平更复杂。我们假设产生的高水平的5HT 通过使用SSRI，可以及时重新平衡各种5HT接收器的表达水平，并通过执行 因此，提供治疗益处。具体而言，我们建议5HTR被5HT激活时， 内吞作用和回收/敏化，而其他人则在溶酶体中被内吞和降解。 SSRI提供的高水平的5HT可以推动5HTR的某些亚型的表达 同时通过其他人保持高水平的信号传导，效果“重新平衡” 5HT信号转移到更多 非常类似于非抑郁状态。在这里，我们将对内吞和全面分析 整个5HTR家族的内吞后特性。值得注意的是，关于 5HTRS的内吞后排序特性。因此，无论结果如何，这些数据都将提供新的 有关SSRI导致5HT水平升高的信息可能会改变受体表达，并可以告知 血清素治疗的新方法旨在重新平衡5HT信号转导。