IP3R mediated Ca2+ release regulates protein metabolism inDrosophilaneuroendocrine cells: implications for development under nutrient stress

Abstract

Successful completion of animal development is fundamentally reliant on nutritional cues. Surviving periods of nutritional insufficiency requires adaptations that are coordinated, in part, by neural circuits. As neuropeptides secreted by neuroendocrine (NE) cells modulate neural circuits, we investigated NE cell function during development under nutrient stress. Starved Drosophila larvae exhibited reduced pupariation if either insulin signaling or IP3/Ca2+ signaling were downregulated in NE cells. Moreover, an IP3R (inositol 1,4,5-trisphosphate receptor) loss-of-function mutant displayed reduced protein synthesis, which was rescued by overexpression of either InR (insulin receptor) or IP3R in NE cells of the mutant, suggesting that the two signaling pathways might be functionally compensatory. Furthermore, cultured IP3R mutant NE cells, but not neurons, exhibited reduced protein translation. Thus cell-specific regulation of protein synthesis by IP3R in NE cells influences protein metabolism. We propose that this regulation helps developing animals survive in poor nutritional conditions.

“ER-Ca2+ sensor STIM regulates neuropeptides required for development under nutrient restriction in Drosophila”

“…The ability to pupariate on nutrient-restricted (NR) media (100mM sucrose) as opposed to a complex mixture of yeast, sugar and corn flour ("normal" food), when transferred in the last stage of larval development (~88 hours post egg laying), was used as a measure of development. Collectively, more than 20 different NPs are made by the NE cells in which reducing SOCE components resulted in poor pupariation upon NR (11). From these NPs, those with established roles in feeding and metabolism were selected and, a curated GAL4-UAS genetic screen undertaken.…”

“…Flies were grown at 25 o C in 12h:12h L:D cycle. Recipe for normal food (11). For nutritional stress assay, flies were allowed to lay eggs for 6 hours on normal food.…”

“…In flies (Drosophila melanogaster; Dmel), dSTIM regulates functioning of neurons (7)(8)(9)(10)(11)(12), fat body cells (13) and intestinal stem cells (14). dSTIM-mediated SOCE has been demonstrated in Dmel neurons (7), with functional consequences in certain neuronal subtypes: regulation of flight in dopaminergic neurons (8,15) and development in proteindeprived media in glutamatergic neurons (10).…”

“…Dmel development under nutritional stress was chosen as the biological context to identify SOCE-regulated NPs, for four reasons. First, we previously reported that reducing IP 3 R or dSTIM or expressing a dominant-negative Orai (Orai E180A ), in a large number of Dmel NE cells, reduced larval development under NR conditions (11). Because these manipulations are also known to reduce SOCE in Dmel neurons (7,8), it was likely that SOCE regulates NPs secreted by NE cells that are involved in the adaptation to NR conditions.…”

Modulation of flight and feeding behaviours requires presynaptic IP3Rs in dopaminergic neurons

“…dependant enzymes such as CamKII, previous reports have shown that knock-down of the IP 3 R in Drosophila larval neurons alters their expression profile and specifically affects the expression of several membrane localised ion-channels (Jayakumar et al, 2018). Reduced translation of proteins due to IP 3 R knockdown has also been demonstrated in peptidergic neurons (Megha & Hasan, 2017). Changes in membrane excitability could thus derive from direct regulation of ion channels by Ca 2+ and Ca 2+ dependant enzymes as well as an altered density of specific ion channels.…”