Mechanisms of GPCR-induced Autophagy

GPCR 诱导自噬的机制

• 批准号: 10557029
• 负责人: Joshua Brian Kelley
• 金额: $ 25.95万
• 依托单位: UNIVERSITY OF MAINE ORONO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-05 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10557029
• 关键词: Attenuated; Autophagocytosis; Binding; Cell physiology; Cells; Cellular biology; Cues; Development; Disease; Drug Receptors; Drug Targeting; Endocytosis; Feedback; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; GTP-Binding Protein Regulators; GTP-Binding Proteins; Health; Human; Human Biology; Hyperactivity; Mediating; Molecular; Morphogenesis; Mutation; Organelles; Output; PIK3CG gene; Partner in relationship; Pathway interactions; Pharmaceutical Preparations; Pheromone; Phosphorylation; Physiological; Process; Proteins; Receptor Activation; Receptor Signaling; Recording of previous events; Recycling; Regulation; Research; Role; Signal Induction; Signal Pathway; Signal Transduction; Stress; System; Testing; Tissues; Ubiquitin family; Vacuolar Protein Sorting; Vacuole; Visualization; Yeast Model System; Yeasts; cell behavior; cell growth regulation; combat; combinatorial; desensitization; detector; epsin; extracellular; genetic regulatory protein; human disease; immune function; member; mutant; novel; novel strategies; receptor; receptor internalization; response; sorting nexins; spatiotemporal; stressor; tumor progression; yeast genetics

G-protein coupled receptors (GPCRs) commonly detect extracellular signals to control cellular responses. In many cases, GPCRs detect stresses that lead to activation of the cellular recycling process called autophagy. In the yeast mating pathway, GPCRs are used to detect and grow towards potential mating partners. The mating pathway initiates autophagy, despite the lack of an external stress. We hypothesize that GPCR activation of autophagy represents a novel negative feedback loop that reduces GPCR signaling through enhanced degradation of the receptor. In Aim1 we will test the hypothesis that pheromone signaling drives selective autophagy rather than bulk autophagy through a combination of Gα activation of PI3 Kinase and other pheromone specific signals. In Aim 2 we will test the hypothesis that pheromone induced autophagy serves as a negative feedback loop to enhance receptor desensitization. These studies will provide a molecular understanding of the interplay between GPCR signaling and autophagy, two systems that are well conserved between yeast and humans and in which yeast research has a long history of providing meaningful advances in the understanding of human biology. The understanding of GPCR and autophagy interactions is important to understanding the potential combinatorial effects of the myriad GPCR and autophagy targeting drugs currently used to treat human disease.

G 蛋白偶联受体 (GPCR) 通常检测细胞外信号来控制细胞 回应。在许多情况下，GPCR 检测导致细胞激活的压力 回收过程称为自噬。在酵母交配途径中，GPCR 用于检测 并与潜在的伴侣一起成长。交配途径启动自噬，尽管 缺乏外部压力。我们假设 GPCR 激活自噬代表 新型负反馈环路，通过增强降解来减少 GPCR 信号传导 受体。在 Aim1 中，我们将测试信息素信号驱动选择性的假设 通过 Gα 激活 PI3 激酶和 其他信息素特定信号。在目标 2 中，我们将检验信息素诱导的假设 自噬作为负反馈回路增强受体脱敏。这些 研究将从分子角度理解 GPCR 信号传导与 自噬，酵母和人类之间保存完好的两个系统，其中酵母 研究在为理解人类提供有意义的进展方面有着悠久的历史 生物学。了解 GPCR 和自噬相互作用对于理解 目前无数GPCR和自噬靶向药物的潜在组合效应 用于治疗人类疾病。