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Store-Operated Calcium Entry in Müller Glia Is Controlled by Synergistic Activation of TRPC and Orai Channels
- Source :
- The Journal of Neuroscience. 36:3184-3198
- Publication Year :
- 2016
- Publisher :
- Society for Neuroscience, 2016.
-
Abstract
- The endoplasmic reticulum (ER) is at the epicenter of astrocyte Ca2+signaling. We sought to identify the molecular mechanism underlying store-operated calcium entry that replenishes ER stores in mouse Müller cells. Store depletion, induced through blockade of sequestration transporters in Ca2+-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 theTrpc1gene. Ca2+release-activated currents (ICRAC) were identified by ion permeability, voltage dependence, and sensitivity to selective Orai antagonists Synta66 and GSK7975A. Depletion-evoked calcium influx was initiated at the Müller end-foot and apical process, triggering centrifugal propagation of Ca2+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–mitochondrial contacts at the vitreal surface of the end-foot. The mouse retina expresses transcripts encoding bothStimand all knownOraigenes; Müller glia predominantly express stromal interacting molecule 1 (STIM1), whereas STIM2 is mainly confined to the outer plexiform and RGC layers. Elimination of TRPC1 facilitated Müller 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 Müller 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.SIGNIFICANCE STATEMENTStore-operated Ca2+signaling represents a major signaling pathway and source of cytosolic Ca2+in astrocytes. Here, we show that the store-operated response in Müller 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 Ca2+entry-induced transcellular Ca2+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.
- Subjects :
- Male
0301 basic medicine
Ependymoglial Cells
Biology
Endoplasmic Reticulum
Retina
Membrane Potentials
Mice
03 medical and health sciences
Transient receptor potential channel
Glial Fibrillary Acidic Protein
medicine
Animals
Stromal Interaction Molecule 1
Stromal Interaction Molecule 2
TRPC
TRPC Cation Channels
Calcium signaling
Mice, Knockout
Membrane Glycoproteins
Voltage-dependent calcium channel
General Neuroscience
STIM1
Articles
STIM2
Calcium Channel Blockers
Store-operated calcium entry
Cell biology
Mice, Inbred C57BL
Disease Models, Animal
030104 developmental biology
medicine.anatomical_structure
Gene Expression Regulation
Benzamides
Pyrazoles
Calcium
Female
Ocular Hypertension
Calcium Channels
sense organs
Neuroscience
Muller glia
Subjects
Details
- ISSN :
- 15292401 and 02706474
- Volume :
- 36
- Database :
- OpenAIRE
- Journal :
- The Journal of Neuroscience
- Accession number :
- edsair.doi.dedup.....08b02d8870dce5856f236906ce029820