A model for ion channel voltage gating with static S4 segments

Abstract

The voltage gated ion channels (especially for Na+ and K+, with several Ca2+ channels being closely related) of nerve and other membranes have been intensively studied for over 50 years; the gating mechanism is now being worked out, using several different lines of evidence. While the amino acid sequence of the protein which makes up the channels is known, and numerous sites have been mutated, with the mutations studied in a number of ways, there are still fundamental disagreements on the details of the gating mechanism. The protein is a tetramer (approximately), each domain having six transmembrane segments, with the fourth (S4) containing basic amino acids at every third position; the most common mechanism which has been proposed is to have S4 move some distance through the membrane, in the process opening the channel. We wish to propose a different mechanism, in which S4 remains stationary (or almost so). The “gate” is water, held in the pore by hydrogen bonding and by fields of the charges on amino acid side chains. To test this suggestion, we have done calculations which give an estimate of the distribution of the electric field in the water filled pore, Monte Carlo simulations of the behavior of the water in the pore, and ab initia proton tunneling calculations of a model system; we suggest the mechanism for the first step in gating charge motion may be tunneling of a proton. The local field may reach 109Vm-1, and the transmembrane field 107 Vm-1, which are critical for the tunneling. Based on the electric potential calculations, we propose that not all the S4 basic amino acids are positively charged, that protons may be transferred among them, or to water and to acidic amino acids on other segments in the channel. Finally, we consider the consequences of the model for the distribution of the electrical potential at which the first step in gating begins; from this we obtain a reasonable relation between open probability and membrane potential, and an explanation of an experiment (Fohlmeister and Adelman[1]) which has not hitherto been explained in a manner consonant with data available in 1998.