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, and depolarize in response to a light flash. Defects in transmission between photoreceptors and bipolar cells result in several forms of congenital stationary night blindness (CSNB). The incomplete form, CSNB2, results from mutations in genes critical to glutamate release in photoreceptors, including the 11F subunit of voltage dependent calcium channels. The complete form emerges from mutations in signaling in DBCs, which include mutations in mGluR6 and nyctalopin (a protein of unknown function). Signaling through DBCs is mediated via a metabotropic glutamate receptor, mGluR6, which modulates the activity of a non-specific cation channel of unknown identity. The details of this mGluR6 cascade are mostly unknown. The long term goal of this project is to characterize the molecular components required for synaptic transmission between photoreceptors and DBCs. This project has four specific aims: 1) determine the structure/function relationships of nyctalopin, 2) determine the state of the non-specific cation channel in several night blind mice, 3) determine the binding partners of nyctalopin, thereby elucidating new component of the mGluR6 cascade, and 4) create knockout mouse lines of the nyctalopin interacting proteins to determine if they result in nigh blindness. At the completion of this project, we will have identified new members 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 congenital stationary night blindness. They have defects in signal transmission between photoreceptors and the second neuron in the pathway. The studies in this proposal will characterize the nature of the defects and determine new proteins critical to function.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY012354-12
Application #
8135321
Study Section
Special Emphasis Panel (ZRG1-CB-G (90))
Program Officer
Greenwell, Thomas
Project Start
1999-02-01
Project End
2012-12-31
Budget Start
2011-09-01
Budget End
2012-12-31
Support Year
12
Fiscal Year
2011
Total Cost
$399,581
Indirect Cost
Name
University of Louisville
Department
Biochemistry
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
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Sarria, Ignacio; Orlandi, Cesare; McCall, Maureen A et al. (2016) Intermolecular Interaction between Anchoring Subunits Specify Subcellular Targeting and Function of RGS Proteins in Retina ON-Bipolar Neurons. J Neurosci 36:2915-25
Scalabrino, Miranda L; Boye, Sanford L; Fransen, Kathryn M H et al. (2015) Intravitreal delivery of a novel AAV vector targets ON bipolar cells and restores visual function in a mouse model of complete congenital stationary night blindness. Hum Mol Genet 24:6229-39
Qian, Haohua; Ji, Rui; Gregg, Ronald G et al. (2015) Identification of a new mutant allele, Grm6(nob7), for complete congenital stationary night blindness. Vis Neurosci 32:E004
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
Balmer, Jasmin; Ji, Rui; Ray, Thomas A et al. (2013) Presence of the Gpr179(nob5) allele in a C3H-derived transgenic mouse. Mol Vis 19:2615-25
Peachey, Neal S; Pearring, Jillian N; Bojang Jr, Pasano et al. (2012) Depolarizing bipolar cell dysfunction due to a Trpm1 point mutation. J Neurophysiol 108:2442-51
Bojang Jr, Pasano; Gregg, Ronald G (2012) Topological analysis of small leucine-rich repeat proteoglycan nyctalopin. PLoS One 7:e33137
Orlandi, Cesare; Posokhova, Ekaterina; Masuho, Ikuo et al. (2012) GPR158/179 regulate G protein signaling by controlling localization and activity of the RGS7 complexes. J Cell Biol 197:711-9

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