Regulation of Retinal Gap Junctions

University Of Houston, Houston TX

Investigators

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Abstract

Neurons throughout the central nervous system employ two types of synapses, chemical and electrical, to communicate. Electrical synapses, made from gap junction channels, support fast, bidirectional and transmitterless signal transfer between cells that organizes neurons into networks and forms defined and sometimes specialized circuits. Both chemical and electrical synapses display plasticity, which is an essential substrate for local circuit optimization and plays a critical role in learning, behavior and sensory signal processing. The majority of electrical synapses in the mammalian central nervous system are formed by Connexin 36 (Cx36), the product of the GJD2 gene. This connexin is intrinsically capable of functional plasticity through variations in phosphorylation that open or close the channels, and so is dynamically regulated by cellular signaling at the location of the electrical synapse. This project seeks to understand the mechanisms that control this plasticity in neurons of the retina, in which Cx36 plays central roles in rod pathway signal flow and in adaptation of many circuits to different light levels. In chemical synapses, many proteins that regulate function and turnover of neurotransmitter receptors are assembled in the post-synaptic density. In an analogous manner, many proteins that regulate the function of electrical synapses are assembled near them, but our knowledge of these assemblies is minimal. In this project, we will identify proteins that regulate the function and turnover of Cx36 electrical synapses through proteomic strategies. We will harness evolutionary conservation of regulatory mechanisms to identify proteins found to be associated with Cx36 in both mouse and zebrafish retina, and investigate the roles of novel proteins discovered in regulation of Cx36 plasticity and turnover. Key elements of assemblies associated with the electrical synapse are scaffold proteins, which are required for electrical synapse formation and stability. However, our studies indicate that a critical scaffold that binds to Cx36 inhibits its channel function when bound, but that binding to Cx36 is weak. We will investigate the hypothesis that Cx36 is evolutionarily tuned to bind weakly to certain scaffolds and that binding can be further weakened by phosphorylation of sites on Cx36, allowing it to dissociate and enter functional states. Finally, we will investigate whether this modification of Cx36 binding to associated proteins can modulate the size of electrical synapses in a manner that correlates with the electrical synapse functional state. These studies will shed light on mechanisms that regulate the function of electrical synapses in the vertebrate retina, and will provide insight relevant to electrical synapses throughout the central nervous system.