Nitric oxide (NO), carbon monoxide (CO) and cGMP signal transduction systems function in large numbers of retinal neurons. Many biochemical pathways modulate NO and cGMP in normal retinal function and NO is involved in many ocular pathologies. This proposal will test three hypotheses: (1) that specific components of the NO, CO and cGMP signal transduction pathways are found in particular retinal neurons, which will be tested using immunocytochemistry and biochemistry to examine the location and function of particular components of these transduction pathways such as cGMP, guanylate cyclase, phosphodiesterases, heme oxygenases, nitric oxide synthases etc. in specific retinal cells; (2) that ganglion cells of efferents to the retina release NO and use NO as a retrograde transmitter to modulate levels of cGMP in retinal neurons, which will be tested by electrically activating ganglion cells or retinal efferents, followed by cGMP immunocytochemistry and ELISA to monitor changes in cGMP in retinal neurons as well as direct imaging of NO or citrulline immunocytochemistry to localize NO production; and (3) that NO, CO or cGMP can influence several synaptic mechanisms including transmitter release. This will be tested by examining the relationship of NO or cGMP to cGMP-gated channels and protein kinase G, or to the modulation of neurotransmitter release or cellular calcium levels. The investigation of select components of the NO-, CO- or cGMP-related signal transduction pathways in specific retinal cells will provide valuable new knowledge about the function of NO, CO and cGMP in the retina and it will provide a firm anatomical physiological basis for more detailed biochemical, physiological and molecular studies of the function of these signal transduction pathways. Many studies have implicated NO in such diverse ocular pathologies as retinitis, glaucoma, ischemia or excitotoxicity. Increased understanding of the NO-, CO- and cGMP-signaling pathways in both normal and pathological conditions is critical to the development of more selective and effective prophylactic and therapeutic strategies for the treatment of NO-related retinal ocular pathologies.
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