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

神经肽（NPs）在行为和生理中起着至关重要的作用。NP是短蛋白质， 从肽能神经元的大而致密的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 行为，包括进食、社会互动、昼夜节律行为等。一些肽能神经元 可以表达多个NP，并且大多数还含有小的突触囊泡，其释放经典的 神经传递素不同程度的NP处理赋予了额外的复杂性， 可能发生在其释放之前或之后（即受管制的运输、本地化、加工等）。因此，肽能 神经元是可以在神经系统内传递信息的多模态的。此外，一些NPs 也作为神经激素，并且可以向CNS以外的组织发出信号。尽管许多功能 纳米粒已被表征，其受体已被鉴定，但对其活性如何知之甚少。 被调制。 在果蝇中，许多肽能神经元的细胞命运依赖于转录因子的转录。 激活器调光（DIMM）。最近发现，许多DIMM阳性神经元表达G6 P-GAL 4， 表达高度保守的葡萄糖-6-磷酸酶（G6 P）的细胞的标记物，暗示G6 P 在果蝇中有着非典型的作用。G6 P更为人所知的是它在胚胎发生中的作用， 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 以维持动物在食物匮乏时的血糖稳态。果蝇的初步特征 G6 P已经确定表达G6 P的肽能神经元具有致凋亡能力，并且能够 使用丙氨酸作为底物以产生葡萄糖。此外，G6 P是神经细胞中NP积累所必需的。 过程，本申请中提出的初步数据表明，G6 P在这些神经元中是必需的， 产生适当大小的高尔基复合体。根据这些数据，G6 P（并通过推断 被认为在肽能神经元中起着关键作用，推测在神经元的生物发生中， 高尔基体和/或LDCV结构，以影响NP释放，从而调节生理和行为 流程.重要的是，哺乳动物具有三个G6 P基因，其中只有一个（G6 PC 1）参与肝细胞凋亡。 异源发生另外两个基因G6 PC 2和G6 PC 3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G6 P基因的功能尚不清楚，但 考虑到它们在表达和细胞环境方面与果蝇G6 P的相似性， G6 PC 2和G6 PC 3酶在哺乳动物中的作用与果蝇中单一的G6 P酶相似， CNS。 !

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. !