The expression and function of TRPV4 channels in primate retinal ganglion cells and bipolar cells

Abstract

The transient receptor potential vanilloid 4 (TRPV4) channel may be opened by mechanical stimuli to mediate Ca 2+ and Na + influxes, and it has been suggested to mediate glaucoma retinopathy. However, it has been mostly unclear how TRPV4 activities affect the function of primate retinal ganglion cells (RGCs). We studied RGCs and bipolar cells (BCs) in the peripheral retina of the old-world primate using whole-cell current-clamp and voltage-clamp recordings, immunomarkers and confocal microscopy. RGCs were distinguished from displaced amacrine cells (ACs) by the absence of GABA and glycine immunoreactivity and possession of an axon and a large soma in the RGC layer. Strong TRPV4 signal was concentrated in medium to large somas of RGCs, and some TRPV4 signal was found in BCs (including PKCα-positive rod BCs), as well as the end feet, soma and outer processes of Mȕller cells. TRPV4 immunoreactivity quantified by the pixel intensity histogram revealed a high-intensity component for the plexiform layers, a low-intensity component for the soma layers of ACs and Mȕller cells, and both components in the soma layers of RGCs and BCs. In large RGCs, TRPV4 agonists 4α-phorbol 12,13 didecanoate (4αPDD) and GSK1016790A reversibly enhanced the spontaneous firing and shortened the delay of voltage-gated Na + (Nav) currents under current-clamp conditions, and under voltage-clamp conditions, 4αPDD largely reversibly increased the amplitude and frequency of spontaneous excitatory postsynaptic currents. In BCs, changes in the membrane tension induced by either applying pressure or releasing the pressure both activated a transient cation current, which reversed at ~ −10 mV and was enhanced by heating from 24 °C to 30 °C. The pressure for the half-maximal effect was ~18 mmHg. These data indicate that functional TRPV4 channels are variably expressed in primate RGCs and BCs, possibly contributing to pressure-related changes in RGCs in glaucoma.

VEGF-B Is an Autocrine Gliotrophic Factor for Müller Cells under Pathologic Conditions

“…[39][40][41][42]57,58 TRPV4 colocalizes with AQP4 in the end feet of Müller glial cells. 39 Activation of TRPV4 in swollen Müller cells has been reported to contribute significantly to the development of different retinal diseases, such as retinal detachment, 41 glaucomatous retinopathy, 40,57 and photoreceptor death. 41 In this study, although 4-HNE treatment did not alter TRPV4 expression in Müller cells, it significantly disrupted the distribution of actin filaments and altered TRPV4 localization patterns.…”

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

“…26,44,45 Previous studies have shown that TRPV4 channel activation enhances the mEPSC frequency and membrane excitability. 15,19 Surprisingly, TRPV4 channel activation in our study enhanced the inhibitory inputs of RGCs, which may have led to reduced RGC excitability (Figure 3). Because inhibitory inputs in the retina are mediated by GlyRs and GABA A Rs, we examined the effects of TRPV4 channels on these two receptors; our results showed that activation of TRPV4 channels enhanced GlyR-and reduced GABA A Rmediated inputs, suggesting that GlyRs played a major role in modulation of TRPV4 channel-mediated inhibitory inputs under our experimental conditions (Figures 6 and 7).…”

“…15,[59][60][61] In glaucoma, optic disc cupping may stretch RGC axons. 62,63 Therefore, mechanosensitive channels (including TRPV4 channels) might be activated by pathological elevated intraocular pressure 19,64 ; this effect could modulate GlyR-mediated inhibitory inputs. Our study showed that GlyR function and expression were enhanced by TRPV4 channel activation, emphasizing the importance of GlyRs in cell protection 65,66 ; thus, GlyRs may be effective targets for TRPV4 channel-induced modulation of RGC survival in glaucoma.…”

TRPA1 mediates damage of the retina induced by ischemia and reperfusion in mice

“…The presence of various TRP channels in the retina and their importance in vision pathophysiology and other retinal functions have been reported [37][38][39][40] . Studies on the role of TRPV1 in models of retinal damage have led to conflicting results, probably due to the different types of applied insult.…”

“…Whereas TRPV1 activation in retinal explants has been reported to promote cell death, and its inhibition to protect retinal ganglion cells from a hydrostatic pressure insult 41,42 , pharmacological inhibition or genetic deletion of this channel has also been reported to exacerbate the IOP-related damage after 5 weeks 43 . TRPV4 expression has also been associated with increased excitability in isolated retinal ganglion cells and retinal explants in response to membrane stretch, resulting in intracellular calcium mobilization and cell death 37 . However, neither Trpv1 −/− nor Trpv4 −/− mice were protected against these ill effects.…”