Abstract
Purpose: :
Strategies to prevent retinal ganglion cell (RGC) death and vision loss could improve outcomes for people suffering impaired vision caused by disease or injury. Studies suggest that the effects of somatostatin in the retina could be beneficial in some disease conditions. The aim of the present study was to determine the effects of somatostatin on membrane currents in RGCs, the only cells in the retina expressing sst4, to confirm whether neuroprotective actions were evoked.
Methods: :
Whole-cell patch clamp electrophysiological investigations of isolated rat RGCs, RGCs in rat retinal slices and ratiometric Ca2+ imaging of rat retinal flatmounts were carried out.
Results: :
Administration of a selective sst4 agonist (L-803,087) increased outward K+ channel currents by 51 ± 13% and reduced the generation of repetitive action potentials. Ca2+ channel currents (ICa) were suppressed by L-803,087 by 32 ± 9%. Administration of ω-connotoxin GVIA reduced ICa in isolated RGCs by 43 ± 7% and the addition of L-803,087 further reduced ICa by 28 ± 16%. However, RGCs treated first with nifedipine, which blocked 46 ± 4% of ICa, did not show any further reduction in ICa in the presence of L-803,087 (-4 ± 4%). Fura-2 was used to measure changes in intracellular Ca2+ in RGCs in response to high K+-induced depolarization. Results showed that intracellular Ca2+ was increased to a lesser extent in the presence of L-803,087 (67 ± 3%) compared to recordings made in the absence of drug.
Conclusions: :
The present study shows that sst4 stimulation in RGCs reduces excitability by enhancing outward K+ currents, and reduces depolarization-induced influx of Ca2+ into RGCs by directly suppressing L-type ICa. As elevated levels of intracellular Ca2+ are thought to be pro-apoptotic, it is possible that reducing Ca2+ influx into RGCs by stimulating sst4 may be neuroprotective. Thus, targeting sst4 signaling pathways has the potential to reduce vision loss caused by RGC death.
Keywords: ganglion cells • ion channels • neuropeptides