title: TRPV4 regulates calcium homeostasis, cytoskeletal remodeling, conventional outflow and intraocular pressure in the mammalian eye.
abstract: An intractable challenge in glaucoma treatment has been to identify druggable targets within the conventional aqueous humor outflow pathway, which is thought to be regulated/dysregulated by elusive mechanosensitive protein(s). Here, biochemical and functional analyses localized the putative mechanosensitive cation channel TRPV4 to the plasma membrane of primary and immortalized human TM (hTM) cells, and to human and mouse TM tissue. Selective TRPV4 agonists and substrate stretch evoked TRPV4-dependent cation/Ca(2+) influx, thickening of F-actin stress fibers and reinforcement of focal adhesion contacts. TRPV4 inhibition enhanced the outflow facility and lowered perfusate pressure in biomimetic TM scaffolds populated with primary hTM cells. Systemic delivery, intraocular injection or topical application of putative TRPV4 antagonist prodrug analogs lowered IOP in glaucomatous mouse eyes and protected retinal neurons from IOP-induced death. Together, these findings indicate that TRPV4 channels function as a critical component of mechanosensitive, Ca(2+)-signaling machinery within the TM, and that TRPV4-dependent cytoskeletal remodeling regulates TM stiffness and outflow. Thus, TRPV4 is a potential IOP sensor within the conventional outflow pathway and a novel target for treating ocular hypertension.
authors: Department of Ophthalmology &Visual Sciences, Moran Eye Institute, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.|Interdepartmental Program in Neuroscience, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
authors: Daniel A
authors: DA
authors: Ryskamp
authors: Department of Ophthalmology &Visual Sciences, Moran Eye Institute, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
authors: Amber M
authors: AM
authors: Frye
authors: Department of Ophthalmology &Visual Sciences, Moran Eye Institute, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
authors: Tam T T
authors: TT
authors: Phuong
authors: Department of Ophthalmology &Visual Sciences, Moran Eye Institute, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
authors: Oleg
authors: O
authors: Yarishkin
authors: Department of Ophthalmology &Visual Sciences, Moran Eye Institute, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
authors: Andrew O
authors: AO
authors: Jo
authors: Department of Medicinal Chemistry, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
authors: Yong
authors: Y
authors: Xu
authors: Department of Ophthalmology &Visual Sciences, Moran Eye Institute, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.|Interdepartmental Program in Neuroscience, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
authors: Monika
authors: M
authors: Lakk
authors: Department of Ophthalmology &Visual Sciences, Moran Eye Institute, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.|Interdepartmental Program in Neuroscience, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
authors: Anthony
authors: A
authors: Iuso
authors: Department of Ophthalmology &Visual Sciences, Moran Eye Institute, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.|Interdepartmental Program in Neuroscience, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
authors: Sarah N
authors: SN
authors: Redmon
authors: Department of Ophthalmology &Visual Sciences, Moran Eye Institute, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
authors: Balamurali
authors: B
authors: Ambati
authors: Department of Ophthalmology &Visual Sciences, Moran Eye Institute, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.|Center for Translational Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
authors: Gregory
authors: G
authors: Hageman
authors: Department of Medicinal Chemistry, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.
authors: Glenn D
authors: GD
authors: Prestwich
authors: Glauconix, Inc., Albany, NY, USA.
authors: Karen Y
authors: KY
authors: Torrejon
authors: Department of Ophthalmology &Visual Sciences, Moran Eye Institute, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.|Interdepartmental Program in Neuroscience, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.|Center for Translational Medicine, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.|Department of Neurobiology &Anatomy, University of Utah School of Medicine, Salt Lake City, UT 84132, USA.|Department of Bioengineering, University of Utah, Salt Lake City, UT 84112, USA.
authors: David
authors: D
authors: Križaj
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D007429:Intraocular Pressure; D051379:Mice; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology; D009798:Ocular Hypertension / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism*; D014129:Trabecular Meshwork / Q000166:cytology / Q000502:physiology*
chemical_list: C573308:HC-067047; D009025:Morpholines; D011758:Pyrroles; D050916:TRPV Cation Channels; C416986:TRPV4 protein, human; C486576:Trpv4 protein, mouse; D002118:Calcium