Vision begins when light is converted to an electrical signal in the photoreceptors. Increases in light decrease release of the neurotransmitter, glutamate, from cone and rod photoreceptor terminals, and decreases in light increase its release. These changes in synaptic glutamate concentration are detected by two classes of bipolar cells that then transmit the signal vertically through the retinal circuit to the ganglion cells. The neurotransmitter changes also are detected by horizontal cells that provide lateral transmission in the form of feedback and feedforward inhibition. There are two classes of bipolar cells, hyperpolarizing (HBCs) and depolarizing (DBCs). HBCs utilize ionotropic glutamate receptors and hyperpolarize in response to a light flash. DBCs utilize a metabotropic glutamate receptor, mGluR6, that signals to TRPM1, depolarizing in response to a light flash. Defects in transmission in DBCs results in complete congenital stationary night blindness (cCSNB). Mutations in GRM6, NYX, TRPM1 and GPR179 cause cCSNB. The mechanism by which mGluR6 signals TRPM1 is largely unknown. The long term goal of this project is study the molecular interactions between two recently discovered retinal components, GPR179 and Cav1.1, and the other DBC signal transduction components.
The specific aims are: 1) Determine the role of GPR179 in DBC signalplex assembly/function, 2) determine the role of Cav1.1 in DBC signalplex assembly and function, and 3) Determine functional and trafficking interdependence of DBC signalplex components. At the completion of this project, we will have characterized the function of newly discovered proteins (GPR179 and Cav1.1) critical to signal transmission in DBCs. Further, we will have identified new candidate genes for congenital stationary night blindness.

Public Health Relevance

Vision requires a light signal to be converted to an electrical signal, which is then transmitted to the brain via a neuronal network. The group of diseases being studied is referred to as complete congenital stationary night blindness. They have defects in signal transmission between photoreceptors and the second order neurons in the pathway. The studies in this proposal will characterize the nature of the defects and determine new proteins critical to function. Such knowledge is essential to future efforts to restore normal vision. PUBLIC HEALTH RELEVANCE: Vision requires a light signal be converted to an electrical signal, which is then transmitted to the brain via a neuronal network. The diseases being studied are referred to as congenital stationary night blindness. The studies in this proposal will characterize the nature of the defects and determine the function of newly identified proteins critical for normal vision, which will set the stage of therapeutic approaches in the future.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY012354-13
Application #
8439399
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Greenwell, Thomas
Project Start
1999-02-01
Project End
2016-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
13
Fiscal Year
2013
Total Cost
$493,713
Indirect Cost
$164,571
Name
University of Louisville
Department
Biochemistry
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
Ray, Thomas A; Heath, Kathryn M; Hasan, Nazarul et al. (2014) GPR179 is required for high sensitivity of the mGluR6 signaling cascade in depolarizing bipolar cells. J Neurosci 34:6334-43
Klooster, Jan; van Genderen, Maria M; Yu, Minzhong et al. (2013) Ultrastructural localization of GPR179 and the impact of mutant forms on retinal function in CSNB1 patients and a mouse model. Invest Ophthalmol Vis Sci 54:6973-81
Peachey, Neal S; Ray, Thomas A; Florijn, Ralph et al. (2012) GPR179 is required for depolarizing bipolar cell function and is mutated in autosomal-recessive complete congenital stationary night blindness. Am J Hum Genet 90:331-9
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