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Store depletion, induced through blockade of sequestration transporters in Ca<jats:sup>2+<\/jats:sup>-free saline, induced synergistic activation of canonical transient receptor potential 1 (TRPC1) and Orai channels. Store-operated TRPC1 channels were identified by their electrophysiological properties, pharmacological blockers, and ablation of the<jats:italic>Trpc1<\/jats:italic>gene. Ca<jats:sup>2+<\/jats:sup>release-activated currents (<jats:italic>I<\/jats:italic><jats:sub>CRAC<\/jats:sub>) were identified by ion permeability, voltage dependence, and sensitivity to selective Orai antagonists Synta66 and GSK7975A. Depletion-evoked calcium influx was initiated at the M\u00fcller end-foot and apical process, triggering centrifugal propagation of Ca<jats:sup>2+<\/jats:sup>waves into the cell body. EM analysis of the end-foot compartment showed high-density ER cisternae that shadow retinal ganglion cell (RGC) somata and axons, protoplasmic astrocytes, vascular endothelial cells, and ER\u2013mitochondrial contacts at the vitreal surface of the end-foot. The mouse retina expresses transcripts encoding both<jats:italic>Stim<\/jats:italic>and all known<jats:italic>Orai<\/jats:italic>genes; M\u00fcller glia predominantly express stromal interacting molecule 1 (STIM1), whereas STIM2 is mainly confined to the outer plexiform and RGC layers. Elimination of TRPC1 facilitated M\u00fcller gliosis induced by the elevation of intraocular pressure, suggesting that TRPC channels might play a neuroprotective role during mechanical stress. By characterizing the properties of store-operated signaling pathways in M\u00fcller cells, these studies expand the current knowledge about the functional roles these cells play in retinal physiology and pathology while also providing further evidence for the complexity of calcium signaling mechanisms in CNS astroglia.<\/jats:p><jats:p><jats:bold>SIGNIFICANCE STATEMENT<\/jats:bold>Store-operated Ca<jats:sup>2+<\/jats:sup>signaling represents a major signaling pathway and source of cytosolic Ca<jats:sup>2+<\/jats:sup>in astrocytes. Here, we show that the store-operated response in M\u00fcller cells, radial glia that perform key structural, signaling, osmoregulatory, and mechanosensory functions within the retina, is mediated through synergistic activation of transient receptor potential and Orai channels. The end-foot disproportionately expresses the depletion sensor stromal interacting molecule 1, which contains an extraordinarily high density of endoplasmic reticulum cisternae that shadow neuronal, astrocytic, vascular, and axonal structures; interface with mitochondria; but also originate store-operated Ca<jats:sup>2+<\/jats:sup>entry-induced transcellular Ca<jats:sup>2+<\/jats:sup>waves that propagate glial excitation into the proximal retina. These results identify a molecular mechanism that underlies complex interactions between the plasma membrane and calcium stores, and contributes to astroglial function, regulation, and response to mechanical stress.<\/jats:p>","DOI":"10.1523\/jneurosci.4069-15.2016","type":"journal-article","created":{"date-parts":[[2016,3,16]],"date-time":"2016-03-16T18:32:17Z","timestamp":1458153137000},"page":"3184-3198","source":"Crossref","is-referenced-by-count":66,"title":["Store-Operated Calcium Entry in M\u00fcller Glia Is Controlled by Synergistic Activation of TRPC and Orai 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