Abstract
The transient receptor potential vanilloid 4 (TRPV4) channel may be opened by mechanical stimuli to mediate Ca2+ 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.
Highlights
Glaucoma is a retinal disease, characterized by the axon injury and soma loss of retinal ganglion cells (RGCs)
Clusters of large transient receptor potential vanilloid 4 (TRPV4) puncta were observed in the cytosol of large and medium somas of RGCs (≥15 μm in diameter)[42,43], in the perinuclear region, presumably in the rough endoplasmic reticulum where proteins are synthesized
TRPV4 is a pressure-sensitive warm sensor, and our results showed that BCs responded to both pressure and warm temperature
Summary
Glaucoma is a retinal disease, characterized by the axon injury and soma loss of retinal ganglion cells (RGCs). It is a leading cause of blindness worldwide[1], but its exact pathological mechanism is still uncertain. Glaucoma is involved with multiple risk factors, such as biochemical cascades, genetic defects, apoptotic cell death, glutamate excitotoxicity, free radical injury, mitochondria damage, glial activation, etc., while the elevation of the intraocular damages RGCs has been debated. MSCs have been found in multiple types of retinal cells and postulated to contribute to glaucoma retinopathy[5,6], one of which is the transient receptor potential channel (TRP) vanilloid 4 (TRPV4)[7,8]. Mutations in TRPV4 have been linked to axonal neuropathies in patients[9], but the Official journal of the Cell Death Differentiation Association
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