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W.D. Eldred, D. Yu; Glycine and GABA Interact to Regulate the Nitric Oxide/cGMP Signaling Pathway in Retina . Invest. Ophthalmol. Vis. Sci. 2005;46(13):3451.
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Purpose: Nitric oxide (NO) is a free radical that is important in retinal signal transduction and cyclic guanosine monophosphate (cGMP) is a critical downstream messenger of NO. The NO/cGMP signaling pathway can modulate neurotransmitter release and gap junction coupling in horizontal cells and amacrine cells, and increases the gain of the light response in photoreceptors. However, many of the synaptic mechanisms controlling the retinal production of NO and cGMP remain unclear. Methods: This study used GABAergic and glycinergic antagonists in combination with cGMP immunocytochemistry and NO imaging to investigate how the inhibitory GABAergic and glycinergic systems modulate the production of NO and cGMP. Results: Our data show that blocking glycine receptors (GLYR) with strychnine (STRY) produced moderate increases in cGMP like immunoreactivity (cGMP LI) in select types of amacrine and bipolar cells, and a strong increase in NO induced fluorescence (NO IF). TPMPA, a selective GABACR antagonist, greatly reduced the increases in cGMP LI stimulated by STRY, but did not affect the increase in NO IF stimulated by STRY. Bicuculline (BIC), a GABAAR antagonist, however, enhanced the increases in both the cGMP LI and NO IF stimulated by STRY. Finally, double labeling of NO stimulated cGMP and either GLY or GABA indicated that cGMP predominantly colocalized with GLY. Conclusions: Taken together, these findings support the hypothesis that GLY and GABA interact in the regulation of the NO/cGMP signaling pathway, where GLY primarily inhibits NO production and GABA has a greater effect on cGMP production. Such a serial inhibitory pathway may help to shape the course of signal transduction of the NO/cGMP pathway under different physiological situations.
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