@article {140644, title = {Orai-mediated calcium entry determines activity of central dopaminergic neurons by regulation of gene expression.}, journal = {Elife}, volume = {12}, year = {2024}, month = {2024 Jan 30}, abstract = {

Maturation and fine-tuning of neural circuits frequently require neuromodulatory signals that set the excitability threshold, neuronal connectivity, and synaptic strength. Here, we present a mechanistic study of how neuromodulator-stimulated intracellular Ca signals, through the store-operated Ca channel Orai, regulate intrinsic neuronal properties by control of developmental gene expression in flight-promoting central dopaminergic neurons (fpDANs). The fpDANs receive cholinergic inputs for release of dopamine at a central brain tripartite synapse that sustains flight (Sharma and Hasan, 2020). Cholinergic inputs act on the muscarinic acetylcholine receptor to stimulate intracellular Ca release through the endoplasmic reticulum (ER) localised inositol 1,4,5-trisphosphate receptor followed by ER-store depletion and Orai-mediated store-operated Ca entry (SOCE). Analysis of gene expression in fpDANs followed by genetic, cellular, and molecular studies identified Orai-mediated Ca entry as a key regulator of excitability in fpDANs during circuit maturation. SOCE activates the transcription factor trithorax-like (Trl), which in turn drives expression of a set of genes, including , that encodes a histone 3 lysine 36 methyltransferase (H3K36me3). Set2 function establishes a positive feedback loop, essential for receiving neuromodulatory cholinergic inputs and sustaining SOCE. Chromatin-modifying activity of Set2 changes the epigenetic status of fpDANs and drives expression of key ion channel and signalling genes that determine fpDAN activity. Loss of activity reduces the axonal arborisation of fpDANs within the MB lobe and prevents dopamine release required for the maintenance of long flight.

}, keywords = {Calcium, Calcium, Dietary, Cholinergic Agents, Dopamine, Dopaminergic Neurons, Histone-Lysine N-Methyltransferase}, issn = {2050-084X}, doi = {10.7554/eLife.88808}, author = {Mitra, Rishav and Richhariya, Shlesha and Hasan, Gaiti} } @article {107012, title = {Store-operated Ca2+ entry regulates neuronal gene expression and function.}, journal = {Curr Opin Neurobiol}, volume = {73}, year = {2022}, month = {02/2022}, pages = {102520}, abstract = {

Recent studies with mutants of STIM and Orai have identified store-operated Ca2+ entry as an important regulator of neuronal function in Drosophila and mouse. Cellular Ca2+ imaging and electrophysiological studies demonstrate changes in ion channel function in neurons with loss of store-operated Ca2+ entry. Importantly, such changes are specific to neuronal subtypes. Transcriptomic and single-cell gene expression studies from the mouse brain identified wide, and isoform-specific differences, in expression of genes required for ER-store Ca2+ release and store-operated Ca2+ entry, across different neuronal classes. Loss of store-operated Ca2+ entry in neurons impacts neuronal gene expression profiles and includes genes encoding ion channels. The functional significance of store-operated Ca2+ entry across specific neuronal subtypes and in the context of neurodegenerative syndromes needs further study.

}, doi = {10.1016/j.conb.2022.01.005}, author = {Mitra, Rishav and Hasan, Gaiti} } @article {94543, title = {IP3-mediated Ca2+ signals regulate larval to pupal transition under nutrient stress through the H3K36 methyltransferase Set2.}, journal = {Development}, volume = {148}, year = {2021}, month = {2021 Jun 01}, abstract = {

Persistent loss of dietary protein usually signals a shutdown of key metabolic pathways. In Drosophila larvae that have reached a {\textquoteright}critical weight{\textquoteright} and can pupariate to form viable adults, such a metabolic shutdown would needlessly lead to death. Inositol 1,4,5-trisphosphate-mediated calcium (IP3/Ca2+) release in some interneurons (vGlutVGN6341) allows Drosophila larvae to pupariate on a protein-deficient diet by partially circumventing this shutdown through upregulation of neuropeptide signaling and the expression of ecdysone synthesis genes. Here, we show that IP3/Ca2+ signals in vGlutVGN6341 neurons drive expression of Set2, a gene encoding Drosophila Histone 3 Lysine 36 methyltransferase. Furthermore, Set2 expression is required for larvae to pupariate in the absence of dietary protein. IP3/Ca2+ signal-driven Set2 expression upregulates key Ca2+-signaling genes through a novel positive-feedback loop. Transcriptomic studies, coupled with analysis of existing ChIP-seq datasets, identified genes from larval and pupal stages that normally exhibit robust H3K36 trimethyl marks on their gene bodies and concomitantly undergo stronger downregulation by knockdown of either the intracellular Ca2+ release channel IP3R or Set2. IP3/Ca2+ signals thus regulate gene expression through Set2-mediated H3K36 marks on select neuronal genes for the larval to pupal transition.

}, issn = {1477-9129}, doi = {10.1242/dev.199018}, author = {Mitra, Rishav and Richhariya, Shlesha and Jayakumar, Siddharth and Notani, Dimple and Hasan, Gaiti} }