Isolation of congenital stationary night blindness genes

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DESCRIPTION (provided by applicant): Under dark-adapted conditions, glutamate is released at a maximal rate at the terminals of rod and cone photoreceptors. The net result of light absorption by outer segment photopigments is to hyperpolarize the photoreceptor and to reduce the rate of glutamate release. This reduction, is detected by glutamate receptors on the second order neurons of the retina, the horizontal and bipolar cells. As ionotropic glutamate receptors are used by horizontal and hyperpolarizing bipolar cells, both of these cell types are maintained in a depolarized state in darkness and are hyperpolarized in response to light. In comparison, depolarizing bipolar cells (DBCs) incorporate a metabotropic glutamate receptor, mGluR6. As a result of an incompletely defined signal transduction cascade, DBCs are hyperpolarized in darkness and depolarize in response to light. To date, only two key proteins of this process have been identified, mGluR6 and Galpha/0, and much of the DBC signal transduction process remains to be elucidated. Nyctalopin is a newly identified protein that appears to play some key role in DBC signal transduction. Mutations in nyctalopin are known to underlie human CSNB 1 and the nob mutant mouse, and both disorders are characterized by a lack of DBC function. The overall goal of the present project is to define the functional role of nyctalopin in DBC activity. This question will be addressed in several complementary experiments. There are three specific aims; 1) Determine the cellular and subcellular location of the nyctalopin protein, 2) Determine the electrophysiological properties of DBCs from nob mice, and 3) Identify proteins that interact with nyctalopin. At the completion of this project, we expect to have a thorough understanding of the role that nyctalopin plays in DBC signal transduction, and to have identified additional proteins involved in this important process.