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

神经肽(NPs)在行为和生理中起着重要作用。NPS是一种短蛋白质，它是 从肽能神经元的大而致密的核心小泡中储存和释放。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、社交、昼夜节律行为和其他。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小泡 神经递质。不同程度的NP处理赋予了额外的复杂性，这 可在其释放之前或之后发生(即受管制的运输、本地化、加工等)。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还会采取行动 也可以作为神经激素，并可以向中枢神经系统以外的组织发送信号。即使许多人的功能 NPS已经被表征，它们的受体也已经被确定，但对它们的活动方式知之甚少 是被调制的。 在果蝇中，许多肽能神经元的细胞命运取决于转录 激活器变暗(DIMM)。最近发现许多DIMM阳性神经元表达G6P-GAL4，一种 细胞表达高度保守的葡萄糖-6-磷酸酶(G6P)的标志，意味着G6P 在果蝇中扮演了一个非典型的角色。G6P更为人所知的是它在糖异生过程中的作用 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 在动物缺乏食物时维持血糖动态平衡。果蝇的初步特征 G6P已经证实，表达G6P的肽能神经元具有糖异生能力，并能够 使用丙氨酸作为底物来产生葡萄糖。此外，G6P是NP在神经中积累所必需的 过程，以及在本申请中提供的初步数据显示，这些神经元中需要G6P来 生成适当大小的高尔基复合体。根据这些数据，G6P(并通过推断 糖异生)被认为在多肽能神经元中发挥关键作用，可能在 高尔基体和/或LDCV结构，影响NP的释放，从而调节生理和行为 流程。重要的是，哺乳动物有三个G6P基因，其中只有一个(G6PC1)与肝脏有关 糖异生作用。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。这些非规范的哺乳动物G6P基因的功能尚不清楚，但 考虑到它们在表达和细胞背景方面与果蝇G6P的相似之处，这是一个有趣的假设 G6PC2和G6PC3酶在哺乳动物中的作用与单一的G6P酶在苍蝇中的作用相似 中枢神经系统。 好了！

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. !