Horizontal cell glutamate receptor modulation by NO: Mechanisms and functional implications for the first visual synapse

Abstract

Neurons of the horizontal cell retinal neural network are subject to modulation by the neurotransmitter nitric oxide (NO). We have examined the effects of NO on glutamate receptor function in isolated horizontal cells from the perch (Perca fluviatilis) using the concentration ramp technique to simultaneously record receptor current and agonist concentration. Dose–response curves for glutamate (0–1 mM) and kainate (0–200 μM) were measured in the presence and absence of 1–2 mM sodium nitroprusside (SNP), 1 mM 8-Br-cGMP, 100 μM cyclothiazide or 200 μM dopamine as modulators. SNP increased the EC₅₀ (i.e. decreased affinity) for glutamate and increased I_max (i.e. increased efficacy), whereas 8-Br-cGMP increased EC₅₀, but not I_max. In the presence of the α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor desensitization blocker cyclothiazide, the SNP-induced increase in EC₅₀ persisted, but the increase in I_max was blocked. The increase in EC₅₀, but not the increase in I_max, was also observed when the non-desensitizing agonist kainate (100–200 μM) was applied in the presence of SNP. When 2 mM SNP and 200 μM dopamine were applied together, they increased I_max (740 vs. 2455 pA) and EC₅₀ (422 vs. 682 μM). Our findings indicate that NO modulates horizontal cell glutamate responses by reducing the affinity of receptors for glutamate while simultaneously increasing the maximal current. The shift in affinity is cGMP-mediated and independent of desensitization. The action of NO on horizontal cell glutamate receptors is distinct from, but synergistic with, that of dopamine. Glutamate receptor modulation by NO qualitatively predicts the action of NO on horizontal cell light responses in situ and may alter transmission at visual synapses according to adaptational conditions.