Structural landscape of photoreceptor synapses

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PROJECT SUMMARY Rod and cone photoreceptors are indispensable for our vision. Their death or dysfunction is an underlying cause for a vast majority of blinding retina conditions. Key to photoreceptor function is the ability to transmit the signal that they generate in response to light to other neurons in the retina for processing of visual signals and their communication to the brain. For this to occur, photoreceptors form elaborate synapses with the downstream neurons, the bipolar cells (BC). Deficits in synaptic communication between photoreceptors and bipolar cells are known to cause congenital stationary blindness in humans, various forms of rod/cone dystrophies and frequent co-morbidity with many other ocular conditions. The long term goal of our collaborative program is to obtain atomic level view of molecular organization of machinery that enable synaptic communication of the photoreceptors with the hope to better understand blinding conditions and devising strategies for their treatment. Recent research from our laboratories and others have identified several molecules critical for the synaptic communication of photoreceptors. We have further discovered that many of these components are scaffolded into macromolecular assemblies that span the synaptic cleft and physically integrate pre-synaptic elements of photoreceptors with post-synaptic receptors in BC. Specifically, we found that the postsynaptic receptor on BC: mGluR6 interacts with two cell-adhesion molecules in photoreceptors: ELFN1 and ELFN2. Furthermore, the machinery that drives excitation of BC in response to synaptic photoreceptor inputs is associated with an orphan receptor GPR179 which in turn is integrated with pre-synaptic cell adhesion-like molecule pikachurin (Pika) in photoreceptors. We also documented that loss of this organization abolishes synaptic transmission leading to night blindness. However, at the moment we know absolutely nothing about structural basis of these trans-synaptic complexes. Proposed studies aim to fill this gap by determining the atomic structures of the key trans-synaptic scaffolds: ELFN1-mGluR6 and Pika-GPR179 complexes and probing their biochemical mechanisms. This will be achieved by highly synergistic international collaboration leveraging expertise in biochemistry and cell biology of photoreceptor synaptic proteins and recent advances in high resolution cryogenic electron microscopy (CryoEM) to obtain high resolution molecular structures of the complexes probing their mechanisms at exceedingly precise level. The premise of this proposal is that understanding synaptic organization of photoreceptors would lead to novel therapeutic strategies for ameliorating blindness.