Project Summary CACNA2D4 is the gene encoding a2d-4, a subunit of Cav1.4 L-type channels that mediate neurotransmitter release from photoreceptor synaptic terminals. Variants in CACNA2D4 are linked to a spectrum of inherited retinal disorders (IRDs) including cone dystrophies and retinitis pigmentosa. The overall goal of the proposed research to gain insight into the pathophysiological mechanisms of CACNA2D4-associated IRDs by illuminating the structure/function relationships of a2d-4. Our central hypothesis is that a2d-4 utilizes distinct molecular determinants to promote the modulation and presynaptic clustering of Cav1.4 in photoreceptors. We will test this hypothesis using state-of-the-art techniques in electrophysiology, optical imaging, and in vivo testing of the structure/function relationships of a2d-4 in mouse photoreceptors. The expected outcomes of the proposed research will contribute to the Pharos mission by shedding light on the localization and function of an understudied ion channel protein. The broader impact of this research is the discovery of mechanisms underlying a2d-4 function that could be targeted in novel disease-modifying therapies.