The long-term goal of this research is to understand the mechanisms controlling Ca2+ signaling at the photoreceptor synapse and their significance for vision. We have identified a family of calmodulin-like Ca2+-binding proteins (CaBPs), one of which (CaBP4) is specifically localized at the synaptic terminals of photoreceptors in the retina and inner hair cells in the ear. CaBP4 associates with and modulates Cav1 (Cav1.4 and Cav1.3) voltage-gated Ca2+ channels that mediate Ca2+-dependent glutamate release at ribbon synapses. CaBP4 undergoes light-dependent phosphorylation which regulates its functional interaction with Cav1 channels. Mice lacking CaBP4 (Cabp4-/-) show a loss of photoreceptor synapses, impaired photoreceptor transmission, and a visual deficit similar to that seen in mice lacking Cav1.4. In addition, human mutations in the genes encoding CaBP4 and Cav1.4 have been linked to incomplete congenital stationary night blindness (CSNB2), which involves visual defects that are consistent with abnormal photoreceptor transmission. We hypothesize that CaBP4 is an integral subunit of photoreceptor Cav1 channels, and that disruption of this interaction causes abnormalities in photoreceptor synapses and visual impairment. The molecular characterization of Cav1/CaBP4 interaction is therefore crucial for understanding Ca2+ signaling in normal vision and in the physiopathology underlying CSNB2. To this end, we will use a multidisciplinary approach to 1) map the subcellular distribution of Cav1 channels and CaBP4 in mouse retina, 2) define the molecular determinants underlying CaBP4/Cav1 interactions and the impact of CSNB2 mutations, 3) elucidate the role of CaBP4/Cav1 interactions in maintaining photoreceptor synapses. These studies will fill a major void in our understanding of factors controlling photoreceptor Cav1 channels and how dysregulation of these channels may lead to CSNB2 and potentially other visual disorders.
This study will provide molecular insights into the factors controlling Ca2+ signals at the photoreceptor synapse and their importance for the proper development and function of the synapse. This research will may reveal how dysregulation of Ca2+ signals leads to CSNB2 and pave the way for the development of new therapies for CSNB2 and other visual disorders.
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