Abstract
Voltage-gated calcium channels control key functions of excitable cells, like synaptic transmission in neurons and the contraction of heart and skeletal muscles. To accomplish such diverse functions, different calcium channels activate at different voltages and with distinct kinetics. To identify the molecular mechanisms governing specific voltage sensing properties, we combined structure modeling, mutagenesis, and electrophysiology to analyze the structures, free energy, and transition kinetics of the activated and resting states of two functionally distinct voltage sensing domains (VSDs) of the eukaryotic calcium channel CaV1.1. Both VSDs displayed the typical features of the sliding helix model; however, they greatly differed in ion-pair formation of the outer gating charges. Specifically, stabilization of the activated state enhanced the voltage dependence of activation, while stabilization of resting states slowed the kinetics. This mechanism provides a mechanistic model explaining how specific ion-pair formation in separate VSDs can realize the characteristic gating properties of voltage-gated cation channels.
Highlights
Voltage-gated calcium channels (CaV) translate membrane depolarization into calcium influx. They contribute to cellular excitability and they couple electrical activity to fundamental cell functions like contraction of heart and skeletal muscle, secretion of neurotransmitters and hormones, and the regulation of gene expression
CaV1.1 is a pseudo-tetrameric channel with a domain-swapped arrangement in which each voltage-sensing domains (VSDs) (S1107 S4) is positioned next to the pore domain (PD; S5-S6) of the adjacent repeat in a clock-wise orientation (Catterall et al, 2017) (Fig. 1B,D)
We modeled the resting state structures of CaV1.1 VSD I and VSD IV, because they represent the two structurally distinguishable classes of VSDs, and because they differentially regulate the specific gating properties of skeletal muscle calcium currents
Summary
Voltage-gated calcium channels (CaV) translate membrane depolarization into calcium influx. They contribute to cellular excitability and they couple electrical activity to fundamental cell functions like contraction of heart and skeletal muscle, secretion of neurotransmitters and hormones, and the regulation of gene expression. Together with voltage-gated sodium channels (NaV), CaVs form a structurally related ion channel superfamily with a four-fold symmetry (Fig. 1A). Their pore-forming 1 subunits are composed of four homologous but non-identical domains (repeats I-IV), each containing six trans-membrane helices (S1-S6). The S5 and S6 helices plus the connecting P loop of all four repeats form the central channel pore with the selectivity filter and the activation gate (Catterall et al, 2020). The S4 helix contains positively charged residues (termed gating charges) in every third position, and its movement across the electric field upon membrane depolarization is thought to initiate the conformational change resulting in channel opening (Catterall et al, 2017)
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