Neural activity alters osmotic gradients favoring cell swelling in retinal Müller cells. This swelling is followed by a regulatory volume decrease (RVD), partially mediated by an efflux of KCl and water. The transient receptor potential channel 4 (TRPV4), a nonselective calcium channel, has been proposed as a candidate for mediating intracellular Ca²⁺ elevation induced by swelling. We previously demonstrated in a human Müller cell line (MIO-M1) that RVD strongly depends on ion channel activation and, consequently, on membrane potential (V_m ). The aim of this study was to investigate if Ca²⁺ influx via TRPV4 contributes to RVD by modifying intracellular Ca²⁺ concentration and/or modulating V_m in MIO-M1 cells. Cell volume, intracellular Ca²⁺ levels, and V_m changes were evaluated using fluorescent probes. Results showed that MIO-M1 cells express functional TRPV4 which determines the resting V_m associated with K⁺ channels. Swelling-induced increases in Ca²⁺ levels was due to both Ca²⁺ release from intracellular stores and Ca²⁺ influx by a pathway alternative to TRPV4. TRPV4 blockage affected swelling-induced biphasic response (depolarization-repolarization), suggesting its participation in modulating V_m changes during RVD. Agonist stimulation of Ca²⁺ influx via TRPV4 activated K⁺ channels hyperpolarizing V_m and accelerating RVD. We propose that TRPV4 forms a signaling complex with Ca²⁺ and/or voltage-dependent K⁺ channels to define resting V_m and V_m changes during RVD. TRPV4 involvement in RVD depends on the type of stimuli and/or degree of channel activation, leading to a maximum RVD response when Ca²⁺ influx overcomes a threshold and activates further signaling pathways in cell volume regulation. J. Cell. Biochem. 118: 2302-2313, 2017. © 2017 Wiley Periodicals, Inc.

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