Mammalian rod and cone photoreceptors are indispensible for vision. They convert light into electrical response, which is then propagated to the downstream neurons, the ON-bipolar cells (ON-BC). Deficits in synaptic communication with the ON-bipolar neurons are known to cause congenital stationary blindness in humans, a condition characterized by poor light sensitivity and frequent co-morbidity with many other ocular conditions. Our long-term goal is to elucidate molecular and cellular mechanisms of signal transmission at photoreceptor to ON-bipolar synapse with the hope to better understand blinding conditions and devising strategies for their treatment. During the last several years we and others have identified a number of molecules that enable synaptic transmission of photoreceptor signals. In addition to canonical pre- and post- synaptic elements that coordinate neurotransmitter release and its reception, these include several cell adhesion-like molecules with poorly understood functions. Intriguingly, our work over the previous funding period suggested that these emerging molecules are engaged in trans-synaptic bridging of presynaptic release machinery of photoreceptors with postsynaptic receptors in the ON-BC. Specifically, we found that the key postsynaptic receptor mGluR6 on ON- BC interacts with a cell-adhesion molecule: ELFN1 in rods and ELFN2 in cones. Similarly, the orphan receptor GPR179 that negatively regulates mGluR6 signaling in the ON-BC interacts with pre-synaptic dystroglycan complex (DGC) in photoreceptors. These observations lead to the central hypothesis of the proposal that precise synaptic communication of photoreceptors with the downstream ON-BC requires assembly of the signaling complex where interactions between individual elements are tightly orchestrated. We plan on testing this hypothesis by pursuing two complementary Specific Aims that will: 1) determine the roles and mechanisms of ELFN proteins in photoreceptors and 2) delineate the organization and function of trans-synaptic DGC-orphan receptor GPR179 complex. The strategy proposed to address these Aims will entail a synergistic combination of biochemical, cell biological, and physiological approaches exploiting a powerful array of precise tools and animal models. Better understanding of synaptic mechanisms of photoreceptors will yield important insights into light sensory function of the retina and may suggest novel nodes of intervention for treating inherited types of night blindness.
Normal vision is hinged on the ability of photoreceptors to transmit their light excitation to downstream neurons in the visual circuit. Failure of this synaptic communication is a leading cause of congenital forms of night blindness. The work proposed herein will yield a clearer understanding of molecular mechanisms by which photoreceptors communicate with other retina neurons. This is expected to increase our understanding of blinding retina diseases and could offer new strategies for their amelioration.
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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|
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