On the Electrically Driven Transition of a Voltage-Sensitive Ion Channel from Insulator to Ion Conductor

Voltage-sensitive ion channels are glycoprotein macromolecules that carry ion currents across membranes of nerve and muscle fibers. The hypothesis presented helps explain the changes that convert an insulating ion channel into an ion conductor, stating that it undergoes a structural transformation on threshold reduction in the voltage across the membrane. Experimental data show that the excitable membrane is a ferroelectric liquid crystal. The Channel Activation by Electrostatic Repulsion hypothesis proposes the following: electrical attractions between boundary surface charges compress the polar channel into a compact smectic phase with induced dipoles. Critical depolarization eliminates surface charges and dipoles, decreasing the dielectric permittivity of the ion channel. This increases the repulsive electrostatic forces between positively charged residues in the four S4 segments. These forces form a selectivity filter dome and cause a proteinquake to a chiral nematic phase. The selectivity filter allows ions to enter as it strips their hydration waters. The permeant ions occupy hydrogen bonds of ion-conducting helices, displacing protons. Disordered regions between adjacent helices form liquid line defects. In the thermal chaos of physiological temperature, a line defect occasionally connects the inner and outer surfaces, forming a transient ion pathway that carries unpredictable surges of permeant ion currents, as observed in experiments. Tests for this hypothesis are proposed.