Modulation of peptidergic neurons by the gluconeogenic enzyme Glucose-6-Phosphatase

糖异生酶葡萄糖 6 磷酸酶对肽能神经元的调节

• 批准号: 10040862
• 负责人: Hubert O Amrein
• 金额: $ 40.9万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-17 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10040862
• 关键词: Affect; Aggressive behavior; Alanine; Alleles; Animal Feed; Animals; Antibodies; Behavior; Behavioral; Biogenesis; Blood Glucose; Brain; Cell physiology; Cells; Data; Dense Core Vesicle; Drosophila genus; Eating; Enzymes; Exploratory/Developmental Grant; Food deprivation (experimental); Foundations; Future; G6PC2 gene; G6PC3 gene; Generations; Genes; Gluconeogenesis; Glucose; Golgi Apparatus; Hemolymph; Homeostasis; Human; Image; Insecta; Investigation; Kidney; Knock-in; Label; Liver; Mammals; Mediating; Metabolism; Methodology; Microscopy; Nervous system structure; Neurohormones; Neurons; Neuropeptides; Neurotransmitters; Output; Partner in relationship; Pathway interactions; Phenotype; Physiological; Physiological Processes; Physiology; Play; Population; Positioning Attribute; Process; Property; Proteins; Public Health; Publishing; Reagent; Research; Resolution; Reticulum; Role; Secretory Cell; Secure; Signal Transduction; Social Interaction; Stains; Starvation; Structure; Synaptic Vesicles; Techniques; Tissues; Transcription Coactivator; Work; base; blood glucose regulation; circadian; experimental study; falls; feeding; fly; gain of function; glucose-6-phosphatase; glycogenolysis; hepatic gluconeogenesis; loss of function; multimodality; mutant; neural circuit; neuropeptide F; novel; pain sensation; promoter; receptor; relating to nervous system; sugar; tool; vesicular release

Neuropeptides (NPs) play crucial roles in behavior and physiology. NPs are short proteins that are stored and released from Large Dense Core Vesicles of peptidergic neurons. Peptidergic neurons activate neural circuits that regulate and modulate a range of physiological processes and impact an array of behaviors, including feeding, social interactions, circadian behavior and others. Some peptidergic neurons can express multiple NPs, and most contain also small Synaptic Vesicles that release classic neurotransmitters. An additional level of complexity is imparted by various degrees of NP processing, which can occur prior or after their release (i.e. regulated transport, localization, processing etc.). Thus, peptidergic neurons are multimodal that can convey information within the nervous system. In addition, some NPs act also as neurohormones and can signal to tissues other than the CNS. Even though the functions of many NPs have been characterized and their receptors have been identified, little is known about how their activity is modulated. In the fruit fly Drosophila, cell fate of many peptidergic neurons is dependent on the transcriptional activator Dimmed (DIMM). The recent discovery that many DIMM positive neurons express G6P-GAL4, a marker for cells expressing the highly conserved enzyme Glucose-6-phosphatase (G6P), implies that G6P has a non-canonical role in Drosophila. G6P is better known for its role in gluconeogenesis, a process restricted to the liver and kidney of mammals, for the generation of glucose from non-carbohydrate precursors to maintain blood glucose homeostasis when animals are food-deprived. Initial characterization of Drosophila G6P has established that G6P-expressing peptidergic neurons have gluconeogenic capacity and are able to use alanine as a substrate to generate glucose. Moreover, G6P is necessary for NP accumulation in neural processes, and preliminary data presented in this application reveal that G6P is required in these neurons to generate appropriately sized Golgi complexes. Based on these data, G6P (and by inference gluconeogenesis) are proposed to play a critical role in peptidergic neurons, presumably in the biogenesis of Golgi and/or LDCV structures, to affect NP release, thereby modulating physiological and behavioral processes. Importantly, mammals harbor, three G6P genes, only one of which (G6PC1) is involved in hepatic gluconeogenesis. The other two genes, G6PC2 and G6PC3, are expressed in secretory cells of other tissues, including the brain and CNS. The function of these non-canonical mammalian G6P genes is not known, but given their similarities to Drosophila G6P with regard to expression and cellular context, it is intriguing to posit that the G6PC2 and G6PC3 enzymes have similar roles in mammals as the single G6P enzyme in the fly CNS. !

神经肽（NP）在行为和生理学中发挥着至关重要的作用。 NP 是短蛋白质， 从肽能神经元的大致密核心囊泡中储存和释放。肽能神经元激活 调节和调节一系列生理过程并影响一系列的神经回路 行为，包括进食、社交互动、昼夜节律行为等。一些肽能神经元 可以表达多个 NP，并且大多数还包含释放经典的小突触囊泡 神经递质。不同程度的 NP 处理赋予了额外的复杂性，这 可能发生在其发布之前或之后（即受监管的运输、本地化、处理等）。因此，肽能 神经元是多模式的，可以在神经系统内传递信息。此外，一些NP的行为 也作为神经激素，可以向中枢神经系统以外的组织发出信号。尽管功能很多 纳米颗粒已被表征，其受体已被识别，但对其活性如何知之甚少 被调制。 在果蝇果蝇中，许多肽能神经元的细胞命运取决于转录 激活器调暗 (DIMM)。最近发现许多 DIMM 阳性神经元表达 G6P-GAL4， 表达高度保守的酶葡萄糖-6-磷酸酶 (G6P) 的细胞标记，意味着 G6P 在果蝇中具有非规范作用。 G6P 因其在糖异生过程中的作用而闻名 仅限于哺乳动物的肝脏和肾脏，用于从非碳水化合物前体产生葡萄糖 当动物缺乏食物时维持血糖稳态。果蝇的初步表征 G6P 已证实表达 G6P 的肽能神经元具有糖异生能力，并且能够 使用丙氨酸作为底物来生成葡萄糖。此外，G6P对于神经元中NP的积累是必需的。 本申请中提供的初步数据表明这些神经元需要 G6P 生成适当大小的高尔基复合体。根据这些数据，G6P（并推断 糖异生）被认为在肽能神经元中发挥关键作用，大概在生物发生中 高尔基体和/或 LDCV 结构，影响 NP 释放，从而调节生理和行为 流程。重要的是，哺乳动物拥有三个 G6P 基因，其中只有一个 (G6PC1) 与肝脏有关 糖异生。另外两个基因 G6PC2 和 G6PC3 在其他组织的分泌细胞中表达， 包括大脑和中枢神经系统。这些非典型哺乳动物 G6P 基因的功能尚不清楚，但 鉴于它们在表达和细胞环境方面与果蝇 G6P 相似，假设 G6PC2 和 G6PC3 酶在哺乳动物中的作用与果蝇中单一 G6P 酶的作用相似 中枢神经系统。 ！