Eliminating Warrantless Assumptions Facilitates Consideration of an Electrostatic Model of Ion-Channel Activation

Abstract

Models of voltage-sensitive ion channels (VSICs) that don’t specify the way reduction in electric field at threshold activation leads to observed outward S4 motions don’t provide satisfactory explanations of voltage sensing [Bezanilla F (2008) Neuron50:456-468]. Current models depend on unrealistic assumptions: screening of charges by a putative water-filled pore, and simple mechanical devices. A gate, screw, paddle or other everyday device cannot physically explain activation of the highly energetic resting channel, a far-from-equilibrium macromolecular system: The α-helix's hydrogen bonds are too weak to support such rigid structures. The energy required to lengthen the H-bonds is provided when the capacitive energy lost in the voltage reduction to threshold does mechanical work on the channel. Similarities exist between excitable membranes and ferroelectrics [Leuchtag HR (1987) J Theor Biol 127:321-340; 127:341-359; (2008) Voltage-Sensitive Ion Channels, Springer]. The ferroelectricity of excitable membranes must originate in the channels, since VSICs are their active components. In ferroelectrics, the dielectric coefficient ε is a function of the electric field. Electrostatic forces are inversely proportional to ε. Evidence from molecules with the sidechains of the branched-chain amino acids isoleucine, leucine and valine shows that their ε becomes remarkably large in a high electric field [Yoshino K, Sakurai T (1991) in: Goodby JW et al. Ferroelectric Liquid Crystals:317-363], comparable to that in a resting channel. According to the Channel Activation by Electrostatic Repulsion (CAbER) model, ε is high at rest potential and drops on depolarization. The consequently increased electrostatic repulsion between positively charged arginine and lysine residues at activation expands the S4 segments. This outward motion reconfigures the VSIC into an “open” structure with pore-domain sites wide enough to accommodate unhydrated permeant ions that hop stochastically across the channel [Leuchtag HR (2016) Biophys. J. 112(3):544a; 112(3):543a-544a].