This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. In the retina, visual information is segregated into pathways that respond to increases and decreases in light intensity. At the first retinal synapse, the tonic release of glutamate from photoreceptor terminals maintains a high synaptic concentration in darkness that decreases in response to light. Two types of postsynaptic cells, the ON- and OFF-bipolar cells, respond with opposite polarity to glutamate released by photoreceptors. The ON-bipolar cell signaling pathway originates with a unique metabotropic glutamate receptor, mGluR6, which is found on the dendrites of ON-bipolar cells. mGluR6 acts via a G-protein, GO, to regulate the activity of an unidentified cation channel such that the light-induced decrease in synaptic glutamate opens the channel and depolarizes the cell. Congenital stationary night blindness (CSNB) is a group of non-progressive retinal diseases characterized by impaired scotopic vision. Mutations in a number of genes have been shown to be associated with CSNB. One such example are mutations in GRM6, the gene encoding mGluR6. Recently, it has been reported that CSNB in Appaloosa horses is associated with a mutation causing a reduced expression of the TRPM1 cation channel. We hypothesized that TRPM1, and possibly other related TRP channels, are the cation channels coupled to mGluR6. Using a combination of biochemical, immunohistochemical, and electrophysiological approaches, we have found that TRPM1 is necessary for the depolarizing light response of ON-bipolar cells, and further that TRPM1 is a component of the cation channel that generates this light response.
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