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. !
Research Narrative This research is relevant to public health because it will lead to the discovery of novel and fundamental processes in neuropeptide signaling which play essential roles in physiology and behavior of all animals, from worms to humans. We discovered that Glucose-6-Phopshatase (G6P), a highly conserved gluconeogenic enzyme, has a novel function in peptidergic neurons in Drosophila nervous system, where it modulates their output to affect a range of physiological and behavioral processes. The use of Drosophila is likely to inform on the functions of two G6P enzymes in mammals of unknown function (encoded by G6PC2 and G6pC3), which share properties with Drosophila G6P in respect to expression and cellular context.
