Structural basis of CaV3.3 calcium channel gating mechanisms

Voltage-gated calcium channels (CaV) control numerous important functions of excitable cells, like muscle contraction, hormone and neurotransmitter secretion, and activity-dependent gene regulation. The voltage-gated calcium channel family consists of ten different genes, and can be divided into two types: high-voltage activated (HVA) and low-voltage activated (LVA) channels. The LVA channels, specifically CaV3.1, CaV3.2, and CaV3.3, are known as T-type channels and have a significant impact on neuronal activity. T-type channels are promising drug targets for the treatment of epilepsy and pain. However, currently available T-type channel blockers lack subtype specificity, which means they affect multiple subtypes of the channels, limiting the drugs effectiveness. T-type channel CaV3.3 was the last calcium channels to be identified and has long been underappreciated in the field. However, recent discoveries have highlighted its role as a disease-causing channel and a potential target for drug development. Recently, the project leader and colleagues for the first time identified the gene for CaV3.3 (CACNA1I) as a disease gene for neurodevelopmental disorders and epilepsy. Building on that discovery, this project seeks to enhance our understanding of T-type channel function in general and uncover the molecular mechanisms underlying the isoform-specific gating properties of CaV3.3 specifically. El Ghaleb will combine state-of-the-art electrophysiology and molecular biology experiments with the use of advanced dynamic models of the complete CaV3.3 structure, as well as several other calcium channels structures. The project has two main goals. The first goal is to investigate the individual parts of CaV3.3, called voltage-sensing domains (VSDs), and understand how they each contribute to the channel`s activity. The hypotheses is that each VSD possesses unique properties and plays a distinct role in the channel`s function. This study represents the first attempt to explore this question in a T-type calcium channel. The second goal focuses on studying the newly discovered role of calcium in modulating the CaV3.3 activity, particularly in the context of disease-causing mutations. By unraveling the unique gating properties of CaV3.3 and studying its calcium-dependent modulation, the project will shed light on the mechanisms underlying neurological diseases such as epilepsy. Physicians and geneticists have already shown great interest in the project, as they regularly discover new potentially disease-causing mutations in the CACNA1I gene in their patients. The comprehensive understanding of the pathogenic mechanisms gained through this study will aid in the functional characterization of these mutations and accurately predict their pathogenicity. Ultimately, Dr. El Ghaleb hopes to pave the way for the development of more targeted and effective treatments, improving the lives of individuals affected by these conditions.