The nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) signal transduction system has physiological functions in every retinal cell type and every retinal cell type can potentially make NO. However, it is not known if visual stimuli modulate NO production in particular cell types. Also, little is known about the underlying synaptic mechanisms, the relative movement or retention of NO from specific cellular sources, and the interactions between NO and other retinal neurotransmitters. This proposal tests four hypotheses: HYPOTHESIS 1- NO production is increased by light through both the ON- and OFF-synaptic pathways. NO imaging indicates many cells can make visually stimulated NO and that both ON- and OFF-synaptic pathways are involved. This will be tested using NO imaging and specific synaptic blockers to anatomically and pharmacologically characterize the cells with visually stimulated NO production. HYPOTHESIS 2- Photoreceptors can release acetylcholine to modulate levels of NO and cGMP in horizontal cells. This will be tested by localizing choline acetyltransferase and nicotinic receptors; using cholinergic agonists to activate NO/cGMP production, and by testing the effects of cholinergic and glutamatergic antagonists on visually stimulated NO/cGMP production. HYPOTHESIS 3 - Nitric oxide is not freely diffusible and there are differences in the retention of nitric oxide produced by different cellular sources. This will be tested using NO imaging, and by using the activation of soluble guanylate cyclase by NO to make cGMP as an independent functional measure of the presence and movement of NO. This will indicate the effective range of NO movement from specific cellular sources and establish precise anatomical limits for interpreting its range of function in retina. HYPOTHESIS 4- NO has reciprocal relationships with GABA, glycine, serotonin, and dopamine, in that NO modulates the release of these neurotransmitters and they in turn can modulate NO production. NO and peroxynitrite can modulate transmitter release by both Ca2+-dependent release systems and by the reversal of Ca2+-independent and Na+-dependent carrier-mediated uptake systems in neurons. Results indicate that NO modulates the neuronal levels of GABA, glycine, and serotonin, and that the selective blocking of GABAergic, glycinergic, and dopaminergic receptors modulates NO/cGMP in retina.
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