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

Neurons of the horizontal cell retinal neural network are subject to modula tion by the neurotransmitter nitric oxide (NO), We have examined the effect s of NO on glutamate receptor function in isolated horizontal cells from th e perch (Perca fluviatilis) using the concentration ramp technique to simul taneously record receptor current and agonist concentration. Dose-response curves for glutamate (0-1 mM) and kainate (0-200 mu M) were measured in the presence and absence of 1-2 mM sodium nitroprusside (SNP), 1 mM 8-Br-cGMP, 100 mu M cyclothiazide or 200 mu M dopamine as modulators. SNP increased t he EC50 (i.e, decreased affinity) for glutamate and increased I-max (i.e. i ncreased efficacy), whereas 8-Br-cGMP increased EC50, but not I-max. In the presence of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor desensitization blocker cyclothiazide, the SNP-induced incr ease 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-des ensitizing agonist kainate (100-200 mu M) was applied in the presence of SN P. When 2 mM SNP and 200 mu M dopamine were applied together, they increase d I-max (740 vs. 2455 pA) and EC50 (422 vs. 682 mu M). Our findings indicat e that NO modulates horizontal cell glutamate responses by reducing the aff inity of receptors for glutamate while simultaneously increasing the maxima l current. The shift in affinity is cGMP-mediated and independent of desens itization. The action of NO on horizontal cell glutamate receptors is disti nct from, but synergistic with, that of dopamine. Glutamate receptor modula tion 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.