Molecular and cellular regulation of CaV2 voltage-gated calcium channels - CaV2 voltage-gated calcium channels mediate calcium influx at presynaptic axon terminals, triggering neurotransmitter release. Genetic variants in CaV2 channels are associated with multiple neurological and neurodevelopmental conditions, including ataxia, seizures, and autism. CaV2 channel levels are upregulated or downregulated in various neurological diseases, injuries, and pathological conditions; however, the molecular mechanisms governing their trafficking and degradation remain largely unknown. Unlike mammals, where multiple genes encode subunits, leading to redundancy and compensatory mechanisms, the nematode C. elegans has a simplified CaV2 channel organization, with each subunit encoded by a single gene. Moreover, impairment in C. elegans CaV2 channels leads to easily observable disruptions in rhythmic body movements, providing measurable indicators of channel function and abundance. Thus, we propose that C. elegans is a rapid and efficient model to identify genes that regulate CaV2 channels. Through an unbiased forward genetic screen in a sensitized background, we identified at least five novel genes that regulate CaV2 channel levels. In this proposal, we aim to molecularly characterize these newly identified genes and elucidate their roles in CaV2 trafficking and degradation. The expected outcomes of this study are to advance our understanding of CaV2 channelopathies and to uncover potential new therapeutic targets for modulating CaV2 channel levels.
