Characterizing the role of voltage-sensing domains of CaV3.3 determining gating properties

Le résumé fourni par la source

Voltage-gated calcium channels are highly functional proteins important for signal transduction and muscle contraction. They consist of four homologous voltage-sensing domains (VSDs), which regulate the opening and closing of a common pore upon depolarization and repolarization. According to this mechanism, the sliding helix hypothesis illustrates the movement of the S4 helices in the VSDs across the membrane electrical field leading to the ion channel opening/closing. However, the VSDs have varying numbers and positions of countercharges and hence, affect the opening and closing thermodynamics and kinetics differently. Novel atomic-resolution structures of voltage-gated calcium and sodium channels characterize the endpoints of the VSD movement upon depolarization, highlighting the S4 helix in the up-state. Yet, resting state structures are not as accessible, since there are only conformations of prokaryotic channels. Thus, understanding the transitions from resting to up-state and vice versa is still elusive. With enhanced sampling molecular dynamics simulations, we tackle this challenge of a CaV3.3 calcium channel applying a membrane potential. Starting from the known up-state, the S4 helices of the four VSDs moved down to the potential resting state (similar to experimental resting state of a bacterial NaVAb channel). The different VSDs show distinct features in their S4 transitions speed, as well as in the occurrence of ionic interactions of gating- and countercharges. Future experimental data will enable the characterization of the individual VSDs and thus will allow us to determine their distinct roles in the regulation of channel gating properties.

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