Communication at the first visual synapse is mediated by L-type voltage-gated Cav1.4 Ca2+ channels. These channels are concentrated in the synaptic terminal beneath the ribbon, an organelle characteristic of synapses employing tonic neurotransmitter release. Mutation of Cav1.4 alters neurotransmission but can also prevent synaptic development. Such defects can present as a variety of visual diseases, including congenital stationary night blindness or cone-rod dystrophy. In this proposal, we will test the hypothesis that Cav1.
4 (Aim 1) and its auxiliary subunits, ?2 (Aim 2) and ?2?4 (Aim 3), are each essential in various ways for synaptic development in photoreceptors. This work will be accomplished using a complementary array of electrophysiological, genetic, biochemical, 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.
In this proposal we will investigate new roles for synaptic calcium channels in the organization and function of the photoreceptor synapse. Results of this work will promote the development of new approaches to treat injuries and diseases of the retina that cause blindness by disrupting synaptic communication.
|Kerov, Vasily; Laird, Joseph G; Joiner, Mei-Ling et al. (2018) ?2?-4 Is Required for the Molecular and Structural Organization of Rod and Cone Photoreceptor Synapses. J Neurosci 38:6145-6160|
|Williams, Brittany; Haeseleer, Françoise; Lee, Amy (2018) Splicing of an automodulatory domain in Cav1.4 Ca2+ channels confers distinct regulation by calmodulin. J Gen Physiol 150:1676-1687|