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Mutations in the CaV1.2 channel pore, such as the I781T channelopathy mutation, predominantly shift the voltage sensor equilibrium towards activation rather than merely destabilizing the channel pore.
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A novel mathematical modeling technique reveals that pore mutations in CaV1.2, including the I781T channelopathy mutation, predominantly affect channel gating by shifting the voltage sensor equilibrium towards activation.
Voltage sensors (VSs) initiate the pore opening and closure in voltage-gated ion channels. Here, we propose a technique for estimation of the equilibrium constant of the up- and downward VS movements and rate constants of pore transitions from macroscopic current kinetics. Bell-shaped voltage dependence of the activation/deactivation time constants and Bolzmann distributions of CaV1.2 activation were analyzed in terms of a circular four-state (rest, activated, open, deactivated) channel model: both dependencies uniquely constrain the model parameters. Neutralization of gating charges in IS4 or IIS4 only slightly affects the equilibrium constant of VS transition while affecting simultaneously the rate constants of pore opening and closure. The application of our technique revealed that pore mutations on IS6-IVS6 segments induce pronounced shifts of the VS equilibrium between the resting (down) and activated (up) position. Analyzing a channelopathy mutation highlighted that the leftward shift of the activation curve induced by I781T on IIS6 is only partially (35 %) caused by a destabilization of the channel pore but predominantly (65 %) by a shifted VS equilibrium towards activation. The algorithm proposed for CaV1.2 may be applicable for calculating rate constants from macroscopic current kinetics in other voltage-gated ion channels.
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Beyl et al. (2013) studied CaV1.2 channel gating (Basic Science). Mutagenesis of CaV1.2 (pore and voltage sensor mutations) vs. Wild-type CaV1.2 was evaluated on Rate constants of pore transitions and equilibrium constant of voltage sensor movements. Mutations in the CaV1.2 channel pore, such as the I781T channelopathy mutation, predominantly shift the voltage sensor equilibrium towards activation rather than merely destabilizing the channel pore.
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