Physiological Uncoupling of Cone Gap Junctions

This project will examine the physiological mechanisms that close cone to cone ‘gap junctions’, preventing spread of cell death. The investigators will use these studies to identify the signaling pathways that change the functional state of cone gap junctions in order to develop pharmacological interventions that close the junctions, reducing the exchange of small molecules between photoreceptors.

Photoreceptors are joined to each other by gap junctions, channels that permit the exchange of small molecules between adjacent cells. During cell death, such as occurs in macular degeneration, death-promoting factors may pass through gap junctions to adjacent cells and trigger death in otherwise healthy adjacent photoreceptors. This process can speed the progression of disease and hasten vision loss. Treatments that close these gap junctions may delay the progression of the disease. This project will examine the physiological mechanisms that close cone-cone gap junctions. By studying the biochemical properties of the cone photoreceptor gap junction protein, connexin35, we can estimate the functional state of the gap junctions. We will now use these studies to identify the signaling pathways that change the functional state of cone gap junctions. This information will be used to develop pharmacological interventions to close cone gap junctions, reducing the exchange of small molecules between photoreceptors. It is hoped that these studies will identify drugs that can be used to close cone gap junctions selectively. Such drugs could provide a treatment strategy that is complementary to existing treatments for macular degeneration by reducing the rate at which the degeneration spreads.