Many retinal diseases are associated with pathological cell swelling, but the underlying etiology remains to be established. A key component of the volume-sensitive machinery, the transient receptor potential vanilloid 4 (TRPV4) ion channel, may represent a sensor and transducer of cell swelling, but the molecular link between the swelling and TRPV4 activation is unresolved. Here, our results from experiments using electrophysiology, cell volumetric measurements, and fluorescence imaging conducted in murine retinal cells and Xenopus oocytes indicated that cell swelling in the physiological range activated TRPV4 in Müller glia and Xenopus oocytes, but required phospholipase A2 (PLA2) activity exclusively in Müller cells. Volume-dependent TRPV4 gating was independent of cytoskeletal rearrangements and phosphorylation. Our findings also revealed that TRPV4-mediated transduction of volume changes is dependent by its N terminus, more specifically by its distal-most part. We conclude that the volume sensitivity and function of TRPV4 in situ depend critically on its functional and cell type-specific interactions.
Keywords: Müller cells; Xenopus oocytes; aquaporin 4 (AQP4); cell swelling; glaucoma; lipid; osmo-sensing; osmo-sensor; phospholipase A2 (PLA2), 5′,6′-epoxy-8Z,11Z,14Z-eicosatrienoic acid (5′,6′-EET); polyunsaturated fatty acid (PUFA); retina; retinal ganglion cells; transient receptor potential channels (TRP channels); transient receptor potential vanilloid 4 (TRPV4); volume sensing; volume sensor.
© 2019 Toft-Bertelsen et al.