G protein signaling pathways in the retina are critically involved in reception and transduction of visual stimuli. The physiological operation of these pathways depends on the tight control provided by the Regulators of G protein signaling (RGS) proteins. Our long term goal is to elucidate molecular and cellular mechanisms of RGS protein function in shaping retina signaling as a necessary prerequisite to understanding visual dysfunctions and therapeutic means of their treatment. At the first visual synapse, G protein cascade driven by mGluR6 receptor, mediates the responses of ON-bipolar cells to light induced changes in neurotransmitter glutamate release from the photoreceptors. The dysregulation of signal transmission in ON-bipolar pathway causes congenital stationary night blindness, a visual disease characterized by the loss of dim vision. The members of the R7 subfamily of RGS protein, RGS7 and RGS11, are specifically concentrated at the ON-bipolar cell synapses where they form physical complexes with their auxiliary subunits G 5, R7BP, and R9AP as well as with the principal receptor, mGluR6. Disruption of R7 RGS proteins or mGluR6 leads to synaptic deficits and abolishes the responses of ON-bipolar cells to light. These observations lead to the central hypothesis of the proposal that components of R7 RGS complexes play essential role in regulating mGluR6 pathway and mediating synapse homeostasis. This hypothesis will be tested by pursuing three complementary Specific Aims: (1) To establish a role of the RGS complexes in functional homeostasis of the first visual synapse, (2) To determine mechanisms underlying selective delivery of the RGS complexes to the ON-BC dendrites, and (3) To understand kinetic requirements of G protein inactivation in the mGluR6 cascade. The strategy proposed to address these aims will entail a synergistic combination of biochemical, molecular biological, electrophysiological, and physiological approaches, each exploiting the existence of a powerful array of reagents and animal models. Better understanding of the RGS protein function and mGluR6 pathway regulation will yield important insights into the general principles of G protein involvement in synaptic transmission events and may suggest novel nodes of intervention for therapeutic strategies designed to treat inherited types of night blindness.

Public Health Relevance

Normal vision is hinged on the function of the intracellular G protein signaling pathways in retina neurons. Dysregulation of these pathways affects fundamental processes including cellular survival, light reception, and synaptic transmission, and is a leading cause of visual disorders and blindness. The work proposed herein will yield a clearer understanding of the molecules involved in the regulation of G protein pathways in the retina and thus will aid in the rational design of effective therapeutic interventions.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY018139-06
Application #
8292590
Study Section
Special Emphasis Panel (ZRG1-BDPE-N (09))
Program Officer
Neuhold, Lisa
Project Start
2007-04-01
Project End
2016-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
6
Fiscal Year
2012
Total Cost
$495,000
Indirect Cost
$245,000
Name
Scripps Florida
Department
Type
DUNS #
148230662
City
Jupiter
State
FL
Country
United States
Zip Code
33458
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Chen, Yu; Palczewska, Grazyna; Masuho, Ikuo et al. (2016) Synergistically acting agonists and antagonists of G protein-coupled receptors prevent photoreceptor cell degeneration. Sci Signal 9:ra74
Xu, Ying; Orlandi, Cesare; Cao, Yan et al. (2016) The TRPM1 channel in ON-bipolar cells is gated by both the α and the βγ subunits of the G-protein Go. Sci Rep 6:20940
Neuillé, Marion; Morgans, Catherine W; Cao, Yan et al. (2015) LRIT3 is essential to localize TRPM1 to the dendritic tips of depolarizing bipolar cells and may play a role in cone synapse formation. Eur J Neurosci 42:1966-75
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Masuho, Ikuo; Ostrovskaya, Olga; Kramer, Grant M et al. (2015) Distinct profiles of functional discrimination among G proteins determine the actions of G protein-coupled receptors. Sci Signal 8:ra123
Sarria, Ignacio; Pahlberg, Johan; Cao, Yan et al. (2015) Sensitivity and kinetics of signal transmission at the first visual synapse differentially impact visually-guided behavior. Elife 4:e06358
Martemyanov, Kirill A (2014) G protein signaling in the retina and beyond: the Cogan lecture. Invest Ophthalmol Vis Sci 55:8201-7
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
Orlandi, Cesare; Cao, Yan; Martemyanov, Kirill A (2013) Orphan receptor GPR179 forms macromolecular complexes with components of metabotropic signaling cascade in retina ON-bipolar neurons. Invest Ophthalmol Vis Sci 54:7153-61

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