We propose to investigate the molecular mechanism of visual transduction in retinal rods and the flow of signals to retinal ganglion cells. Patch clamp methods will he used to ask the following questions about the cGMP-activated cation channel that generates the rod response to light: 1) How does activation of the channel by CGMP regulate the flow of ions through it? Where is the ligand-controlled gate located relative to the cation binding site? 2) Does covalent modification of channels regulate the channel response to cGMP? What signals control modification, and what is the molecular mechanism? 3) What is the radial distribution of cGMP-activated channels on the rod outer segment? 4) By what mechanism do divalent cations such as Ni++ and Zn++ potentiate the channel's response to cGMP? Does potentiation by divalent cations regulate channel sensitivity under physiological conditions? 5) At the single channel level, how do the open state conductances and gating kinetics of the channel depend on cGMP concentration and membrane potential? Using a new multielectrode recording method we will study correlations in the spontaneous and light-evoked spike discharges of retinal ganglion cells, asking: 1) In darkness and dim light, how do the correlations between impulses in nearby retinal ganglion cells depend on cell type, cell separation and time? 2) What is the spatial distribution of ganglion cells of different functional types? 3) What is the response of the ganglion cell population to photoisomerization of a single rhodopsin molecule? Answers to these questions may help to provide a clearer understanding of visual disturbances in disease.
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