Transient receptor potential vanilloid four channels modulate inhibitory inputs through differential regulation of GABA and glycine receptors in rat retinal ganglion cells

Abstract

The transient receptor potential vanilloid 4 (TRPV4) channel is widely distributed in the retina. Activation of the TRPV4 channel enhances excitatory signaling from bipolar cells to retinal ganglion cells (RGCs), thereby increasing RGC firing rate and membrane excitability. In this study, we investigated the effect of TRPV4 channel activation on the miniature inhibitory postsynaptic current (mIPSC) in rat RGCs. Our results showed that perfusion with HC-067047, a TRPV4-channel antagonist, significantly reduced the amplitude of RGC mIPSCs. Extracellular application of the TRPV4 channel agonist GSK1016790A (GSK101) enhanced the frequency and amplitude of mIPSCs in ON- and OFF-type RGCs; pre-application of HC-067047 blocked the effect of GSK101 on mIPSCs. Furthermore, TRPV4 channels were able to enhance the frequency and amplitude of glycine receptor (GlyR)-mediated mIPSCs and inhibit the frequency of type A γ-aminobutyric acid receptor (GABAA R)-mediated mIPSCs. Upon intracellular administration or intravitreal injection of GSK101, TRPV4 channel activation reduced the release of presynaptic glycine and enhanced the function and expression of postsynaptic GlyRs; however, it inhibited presynaptic release of GABA, but did not affect postsynaptic GABAA Rs. Our study results provide insight regarding the effect of TRPV4 channel activation on RGCs and offer a potential interventional target for retinal diseases involving TRPV4 channels.