Continuum Gating Current Models Computed with Consistent Interactions

Abstract

The action potential of nerve and muscle is produced by voltage-sensitive channels that include a specialized device to sense voltage. The voltage sensor depends on the movement of charges in the changing electric field as suggested by Hodgkin and Huxley. Gating currents of the voltage sensor are now known to depend on the movements of positively charged arginines through the hydrophobic plug of a voltage sensor domain. Transient movements of these permanently charged arginines, caused by the change of transmembrane potential V, further drag the S4 segment and induce opening/closing of the ion conduction pore by moving the S4-S5 linker. This moving permanent charge induces capacitive current flow everywhere. Everything interacts with everything else in the voltage sensor and protein, and so it must also happen in its mathematical model. A Poisson-Nernst-Planck (PNP)-steric model of arginines and a mechanical model for the S4 segment are combined using energy variational methods in which all densities and movements of charge satisfy conservation laws, which are expressed as partial differential equations in space and time. The model computes gating current flowing in the baths produced by arginines moving in the voltage sensor. The model also captures the capacitive pile up of ions in the vestibules that link the bulk solution to the hydrophobic plug. Our model reproduces the signature properties of gating current: 1) equality of ON and OFF charge Q in integrals of gating current, 2) saturating voltage dependence in the Q(charge)-voltage curve, and 3) many (but not all) details of the shape of gating current as a function of voltage. Our results agree qualitatively with experiments and can be improved by adding more details of the structure and its correlated movements. The proposed continuum model is a promising tool to explore the dynamics and mechanism of the voltage sensor.