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Brett H. Mueller, II, Raghu Krishnamoorthy, Donald Daudt, III, Hai-Ying Ma, Thomas Yorio; Interaction of Sigma-1 Receptors with Voltage Gated Calcium Channels Attenuates Calcium Response in Primary Retinal Ganglion Cells. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2657.
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© ARVO (1962-2015); The Authors (2016-present)
Sigma-1 receptors (s1rs) exert neuroprotective effects on retinal ganglion cells (RGCs) both in vivo and in vitro. The purpose of this study was to investigate the role s1rs play in controlling calcium dynamics through Voltage Gated Calcium Channels (VGCCs) in primary RGCs.
Primary RGCs were isolated and purified by sequential immunopanning using Thy 1 antibody from P3-P7 Sprague-Dawley rats. Immunocytochemical analysis was performed to analyze the expression level of s1rs in primary RGCs. Calcium imaging was used to measure changes in intracellular calcium after treating the cells with 20mM KCl. In a different set of experiments, intraocular pressure was elevated in one eye of Brown Norway rats and maintained for 2 weeks, while the contralateral eye served as control. Immunohistochemical analysis of s1r expression was performed in retina sections from rats with elevated intraocular pressure (IOP).
Immunocytochemical analysis demonstrated robust expression of s1rs in the soma and neurites of primary RGC cultures. Calcium imaging results showed that s1r ligand, (+)-N-allylnormetazocine hydrochloride [(+)-SKF10047] in primary RGCs inhibited the influx of calcium through VGCCs by 37% (p<0.05). Pretreatment of RGCs with a s1r antagonist, BD10047, potentiated the calcium influx through VGCC by 44% (p<0.05). Using immunohistochemical analysis, an appreciable decrease of s1r expression was observed in retina sections from rats with elevated IOP, compared to control eyes. Since s1rs have been shown to regulate calcium channels, this down-regulation of receptors may contribute to RGC death in rats subjected to increased IOP.
S1r agonist pre-treatment decreased the levels of calcium influx through VGCCs. Additionally, pre-treatment of primary RGCs with a s1r antagonist showed a significant increase in the levels of intracellular calcium influx through VGCCs, suggesting that endogenous s1rs may play a role in calcium homeostasis in RGCs. Down-regulation of s1rs in the retina following IOP elevation, suggests that decreased s1r expression may lead to calcium overload in RGCs making them more susceptible to neurodegeneration following ocular hypertension.
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