Ca2+ channels in retinal photoreceptors

Communication at the first visual synapse is mediated by L-type voltage-gated Cav1.4 Ca2+ channels. These channels are concentrated in the photoreceptor synaptic terminal beneath the ribbon, an organelle characteristic of synapses employing tonic neurotransmitter release. Dysregulation or mislocalization of Cav1.4 inhibits neurotransmission but also prevents synaptic development and maintenance. Such defects can present as a variety of visual diseases, including congenital stationary night blindness. It is not known how the unique localization of Cav1.4 is achieved or how Cav1.4 channels orchestrate the process of photoreceptor synapse assembly and maintenance. In Aim 1 we propose to establish how two Cav1.4 interacting proteins regulate the unique localization of Cav1.4 at photoreceptor synaptic ribbons. In Aims 2 and 3, we will dissect how two aspects of Cav1.4 function, mediation of Ca2+ signals and scaffolding of synaptic proteins, promote the assembly and stabilization of the photoreceptor synapse. This work will be accomplished using a complementary array of electrophysiological, genetic, biochemical, proteomic, and cell biological approaches. The outcomes of this research should have a broad impact by transforming the concept of how Cav1.4 channels contribute to synapse function and disease-triggered remodeling.