title: Swelling and eicosanoid metabolites differentially gate TRPV4 channels in retinal neurons and glia.
abstract: Activity-dependent shifts in ionic concentrations and water that accompany neuronal and glial activity can generate osmotic forces with biological consequences for brain physiology. Active regulation of osmotic gradients and cellular volume requires volume-sensitive ion channels. In the vertebrate retina, critical support to volume regulation is provided by Müller astroglia, but the identity of their osmosensor is unknown. Here, we identify TRPV4 channels as transducers of mouse Müller cell volume increases into physiological responses. Hypotonic stimuli induced sustained [Ca(2+)]i elevations that were inhibited by TRPV4 antagonists and absent in TRPV4(-/-) Müller cells. Glial TRPV4 signals were phospholipase A2- and cytochrome P450-dependent, characterized by slow-onset and Ca(2+) waves, and, in excess, were sufficient to induce reactive gliosis. In contrast, neurons responded to TRPV4 agonists and swelling with fast, inactivating Ca(2+) signals that were independent of phospholipase A2. Our results support a model whereby swelling and proinflammatory signals associated with arachidonic acid metabolites differentially gate TRPV4 in retinal neurons and glia, with potentially significant consequences for normal and pathological retinal function.
authors.affiliation: Department of Ophthalmology & Visual Sciences, Moran Eye Institute, and Interdepartmental Program in Neuroscience, Salt Lake City, Utah 84132.
authors.forename: Daniel A
authors.identifier: http://orcid.org/0000-0002-2197-0730
authors.initials: DA
authors.lastname: Ryskamp
authors.affiliation: Department of Ophthalmology & Visual Sciences, Moran Eye Institute, and.
authors.forename: Andrew O
authors.initials: AO
authors.lastname: Jo
authors.affiliation: Department of Ophthalmology & Visual Sciences, Moran Eye Institute, and.
authors.forename: Amber M
authors.identifier: http://orcid.org/0000-0001-6667-8314
authors.initials: AM
authors.lastname: Frye
authors.affiliation: Department of Ophthalmology & Visual Sciences, Moran Eye Institute, and.
authors.forename: Felix
authors.initials: F
authors.lastname: Vazquez-Chona
authors.affiliation: Department of Cellular and Molecular Medicine, University of Copenhagen, 1165 Copenhagen, Denmark.
authors.forename: Nanna
authors.initials: N
authors.lastname: MacAulay
authors.affiliation: Department of Ophthalmology & Visual Sciences, and Department of Pharmacology and Experimental Neurosciences, University of Nebraska Medical Center, Omaha, Nebraska 68198, and.
authors.forename: Wallace B
authors.initials: WB
authors.lastname: Thoreson
authors.affiliation: Department of Ophthalmology & Visual Sciences, Moran Eye Institute, and Interdepartmental Program in Neuroscience, Salt Lake City, Utah 84132, Department of Neurobiology & Anatomy and Center for Translational Medicine, University of Utah School of Medicine, Salt Lake City, Utah 84132 david.krizaj@hsc.utah.edu.
authors.forename: David
authors.identifier: http://orcid.org/0000-0003-4468-3029
authors.initials: D
authors.lastname: Križaj
mesh_terms: D000818:Animals; D015777:Eicosanoids / Q000378:metabolism*; D005911:Gliosis / Q000473:pathology; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009457:Neuroglia / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D009994:Osmolar Concentration; D018408:Patch-Clamp Techniques; D054467:Phospholipases A2 / Q000502:physiology; D012160:Retina / Q000166:cytology / Q000502:physiology*; D012165:Retinal Ganglion Cells / Q000502:physiology; D050916:TRPV Cation Channels / Q000235:genetics / Q000502:physiology*
chemical_list: D015777:Eicosanoids; D050916:TRPV Cation Channels; C486576:Trpv4 protein, mouse; D054467:Phospholipases A2
keywords: Müller glia; TRP channels; ganglion cell; osmoregulation; retina