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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY026817-04
Application #
9868311
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Greenwell, Thomas
Project Start
2017-03-01
Project End
2022-02-28
Budget Start
2020-03-01
Budget End
2021-02-28
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Iowa
Department
Physiology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
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, Fran├žoise; Lee, Amy (2018) Splicing of an automodulatory domain in Cav1.4 Ca2+ channels confers distinct regulation by calmodulin. J Gen Physiol 150:1676-1687