Molecular Models of Voltage Sensing

Voltage-gated ion channels have always been overachievers. They have the singular distinction of having solved the permeation problem five times over. Not only do they have a central, highly selective pore through which they conduct charged ions, they also have four peripheral “pores” or gating canals through which they conduct the charged portions of their voltage sensors. This trick of protein permeation generates a small gating current as the S4 arginines and lysines move through the electric field of the membrane and ultimately results in channel opening. The membrane-spanning portion of voltage-gated channels contains two classes of functional domains. Four voltage-sensing domains located at the periphery of the tetramer surround a central pore forming domain (Fig. 1 B). The pore domain of the voltage-gated K (Kv) channels share structural homology with the bacterial KcsA and MthK channels whose crystal structures have been solved (Doyle et al., 1998; Jiang et al., 2002). The pore domain consists of S5, the P-loop, and S6 which constitute the ion permeation pathway, including the selectivity filter and two of the gates (Fig. 1). The voltage-sensing domains, whose crystal structures have yet to be determined, are the subject of this Perspective. The four positively charged S4s, located between S1-S3 and the pore domain, function as voltage sensors. Membrane depolarization drives the positively charged residues of S4 through the gating canal. The movement of these charges through the membrane electric field generates the gating current that precedes channel opening. Below, we explore possible models of voltage sensor structure and motion with the ultimate goal of understanding how voltage-sensor rearrangements drive the pore domain gates to open and close. We begin by outlining eight fundamental experimental observations in the field and then discuss models that could account for these observations.