L-and T-type Ca^(2+)channels dichotomously contribute to retinal ganglion cell injury in experimental glaucoma

Retinal ganglion cell apoptotic death is the main pathological characteristic of glaucoma,which is the leading cause of irreversible blindness.Disruption of Ca^(2+)homeostasis plays an important role in glaucoma.Voltage-gated Ca^(2+)channel blockers have been shown to improve vision in patients with glaucoma.However,whether and how voltage-gated Ca^(2+)channels are involved in retinal ganglion cell apoptotic death are largely unknown.In this study,we found that total Ca^(2+)current densities in retinal ganglion cells were reduced in a rat model of chronic ocular hypertension experimental glaucoma,as determined by whole-cell patch-clamp electrophysiological recordings.Further analysis showed that L-type Ca^(2+)currents were downregulated while T-type Ca^(2+)currents were upregulated at the later stage of glaucoma.Western blot assay and immunofluorescence experiments confirmed that expression of the Ca_(V)1.2 subunit of L-type Ca^(2+)channels was reduced and expression of the Ca_(V)3.3 subunit of T-type Ca^(2+)channels was increased in retinas of the chronic ocular hypertension model.Soluble tumor necrosis factor-α,an important inflammatory factor,inhibited the L-type Ca^(2+)current of isolated retinal ganglion cells from control rats and enhanced the T-type Ca^(2+)current.These changes were blocked by the tumor necrosis factor-αinhibitor XPro1595,indicating that both types of Ca^(2+)currents may be mediated by soluble tumor necrosis factor-α.The intracellular mitogen-activated protein kinase/extracellular signal-regulated kinase pathway and nuclear factor kappa-B signaling pathway mediate the effects of tumor necrosis factor-α.TUNEL assays revealed that mibefradil,a T-type calcium channel blocker,reduced the number of apoptotic retinal ganglion cells in the rat model of chronic ocular hypertension.These results suggest that T-type Ca^(2+)channels are involved in disrupted Ca^(2+)homeostasis and apoptosis of retinal ganglion cells in glaucoma,and application of T-type Ca^(2+)channel blockers,especially a specific CaV3.3 blocker,may be a potential strategy for the treatment of glaucoma.