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      When size matters: transient receptor potential vanilloid 4 channel as a volume‐sensor rather than an osmo‐sensor

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          Abstract

          Key points

          • Mammalian cells are frequently exposed to stressors causing volume changes.

          • The transient receptor potential vanilloid 4 (TRPV4) channel translates osmotic stress into ion flux.

          • The molecular mechanism coupling osmolarity to TRPV4 activation remains elusive.

          • TRPV4 responds to isosmolar cell swelling and osmolarity translated via different aquaporins.

          • TRPV4 functions as a volume‐sensing ion channel irrespective of the origin of the cell swelling.

          Abstract

          Transient receptor potential channel 4 of the vanilloid subfamily (TRPV4) is activated by a diverse range of molecular cues, such as heat, lipid metabolites and synthetic agonists, in addition to hyposmotic challenges. As a non‐selective cation channel permeable to Ca 2+, it transduces physical stress in the form of osmotic cell swelling into intracellular Ca 2+‐dependent signalling events. Its contribution to cell volume regulation might include interactions with aquaporin (AQP) water channel isoforms, although the proposed requirement for a TRPV4–AQP4 macromolecular complex remains to be resolved. To characterize the elusive mechanics of TRPV4 volume‐sensing, we expressed the channel in Xenopus laevis oocytes together with AQP4. Co‐expression with AQP4 facilitated the cell swelling induced by osmotic challenges and thereby activated TRPV4‐mediated transmembrane currents. Similar TRPV4 activation was induced by co‐expression of a cognate channel, AQP1. The level of osmotically‐induced TRPV4 activation, although proportional to the degree of cell swelling, was dependent on the rate of volume changes. Importantly, isosmotic cell swelling obtained by parallel activation of the co‐expressed water‐translocating Na +/K +/2Cl cotransporter promoted TRPV4 activation despite the absence of the substantial osmotic gradients frequently employed for activation. Upon simultaneous application of an osmotic gradient and the selective TRPV4 agonist GSK1016790A, enhanced TRPV4 activation was observed only with subsaturating stimuli, indicating that the agonist promotes channel opening similar to that of volume‐dependent activation. We propose that, contrary to the established paradigm, TRPV4 is activated by increased cell volume irrespective of the molecular mechanism underlying cell swelling. Thus, the channel functions as a volume‐sensor, rather than as an osmo‐sensor.

          Key points

          • Mammalian cells are frequently exposed to stressors causing volume changes.

          • The transient receptor potential vanilloid 4 (TRPV4) channel translates osmotic stress into ion flux.

          • The molecular mechanism coupling osmolarity to TRPV4 activation remains elusive.

          • TRPV4 responds to isosmolar cell swelling and osmolarity translated via different aquaporins.

          • TRPV4 functions as a volume‐sensing ion channel irrespective of the origin of the cell swelling.

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          Author and article information

          Contributors
          macaulay@sund.ku.dk
          Journal
          J Physiol
          J. Physiol. (Lond.)
          10.1111/(ISSN)1469-7793
          TJP
          jphysiol
          The Journal of Physiology
          John Wiley and Sons Inc. (Hoboken )
          0022-3751
          1469-7793
          14 May 2017
          01 June 2017
          : 595
          : 11 ( doiID: 10.1113/tjp.2017.595.issue-11 )
          : 3287-3302
          Affiliations
          [ 1 ] Department of Neuroscience and Pharmacology University of Copenhagen Copenhagen Denmark
          [ 2 ] Department of Ophthalmology & Visual Sciences, Moran Eye Institute University of Utah School of Medicine Salt Lake City UT USA
          Author notes
          [*] [* ] Corresponding author N. MacAulay: Department of Neuroscience and Pharmacology, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen N, Denmark. Email:  macaulay@ 123456sund.ku.dk
          Author information
          http://orcid.org/0000-0001-9009-0094
          http://orcid.org/0000-0003-4468-3029
          http://orcid.org/0000-0002-7800-6600
          Article
          PMC6426160 PMC6426160 6426160 TJP12328
          10.1113/JP274135
          6426160
          28295351
          2b016622-29bd-43df-b3ab-f75483ef6803
          © 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society
          History
          : 03 February 2017
          : 07 March 2017
          Page count
          Figures: 8, Tables: 0, Pages: 16, Words: 10525
          Funding
          Funded by: Foundation for the National Institutes of Health
          Award ID: EY022076
          Award ID: P30EY014800
          Funded by: VELUX Foundation
          Award ID: 107493
          Funded by: National Institutes of Health
          Award ID: EY027920
          Funded by: Willard L. Eccles Foundation
          Funded by: Moran Eye Institute
          Categories
          Research Paper
          Molecular and cellular
          Editor's Choice
          Custom metadata
          2.0
          tjp12328
          1 June 2017
          Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.1 mode:remove_FC converted:20.03.2019

          volume regulation,volume‐sensor,water channel,aquaporin,ion channel,osmo‐sensor,osmotic swelling,transient receptor potential vanilloid 4 (TRPV4),TRP channels

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