Activation of the sigma receptor 1 modulates AMPA receptor-mediated light-evoked excitatory postsynaptic currents in rat retinal ganglion cells

Abstract

Purpose: Sigma receptor subtype 1 (σR1) is expressed in most of inner retinal neurons, including ganglion cells (GCs), in rats. AMPA receptor subtype is known to mediate signal transfer from bipolar cells to GCs. We investigated how activation of σR1 modulates AMPA receptor (AMPAR)-mediated light-evoked excitatory postsynaptic currents (L-EPSCs) of ON-type GCs (ON-GCs) and explored possible underlying mechanisms.

Methods: Effects of SKF10047 (SKF), a σR1 agonist, on AMPAR-mediated L-EPSCs of ON-GCs were examined in rat retinal slice preparations by whole-cell patch-clamp recording, combined with calcium imaging techniques, and possible underlying mechanisms were explored by pharmacological manipulations.

Results: Whole cell recording showed that 50 μM SKF significantly suppressed AMPAR-mediated L-EPSCs of ON-GCs and the effect could be reversed by the σR1 antagonist BD1047, suggesting that the SKF effect was mediated by σR1. It was unlikely that the SKF-induced suppression of L-EPSCs was due to a change in glutamate release probability of bipolar cells, because SKF did not change the paired-pulse ratio (PPR) of AMPAR-mediated EPSCs in ON-GCs. The SKF effect was abolished by intracellular dialysis of the G protein inhibitor GDP-β-S and the PKG inhibitor KT5823. SKF did not change the L-EPSCs when GCs were infused by cGMP. SKF did not change intracellular Ca²⁺ ([Ca²⁺]_i) in GCs, and the SKF-induced suppression of L-EPSCs persisted when [Ca²⁺]_i was chelated by BAPTA. Furthermore, SKF persisted to suppress the L-EPSCs when PKA and PI-PLC signaling pathways were blocked.

Conclusions: Activation of σR1 suppresses AMPAR-mediated L-EPSCs, which is mediated by a distinct calcium-independent cGMP-PKG signaling pathway.