These questions are not only central to studies of channels from “classically” investigated types, such as VGICs, LGICs, and glutamate receptors, but are even more pressing for less well-understood

channels built on alternative trimeric scaffolds, such as P2X receptors (Jiang et al., 2013) and ASICs (Wemmie et al., 2013), and channels that respond to temperature C646 clinical trial (Nilius and Owsianik, 2011) and mechanical force (Coste et al., 2012, Kim et al., 2012 and Yan et al. 2013). A beautiful illustration of the iterative nature of scientific progress on ion channels and of the way that new methods enable definitive experiments to be done is the story of voltage sensing. Having resolved the voltage-dependent sodium and potassium conductances selleck chemicals in voltage-clamp studies in the 1940s and 1950s, Hodgkin and Huxley simulated the complex dynamics by which the conducting devices of the squid giant axon membrane turn on and off to generate the action

potential (Hodgkin and Huxley, 1952). They recognized that to sense voltage the devices needed to have a charge (perhaps an ion captured from solution) in the plane of the membrane that would be displaced inward and outward by changes in the membrane electric field. It took 20 years until Armstrong and Bezanilla measured the very small current that is generated by the motion of this “gating charge” (Armstrong and Bezanilla, 1973). While evidence accumulated over the years that the conducting devices are made of protein, it

took the invention of single-channel patch-clamp recording (Hamill et al., 1981) to show that the mechanism of conduction through the best-known conductors was too fast for a transporter and must be flux through a pore (Hille, 2001). The cloning of the first voltage-gated sodium and potassium channels in the mid- to late 1980s led to the discovery of the strange S4 segment, the only Parvulin sequence motif similarity between sodium and potassium channels: a repeat with several arginine residues spaced at intervals of three, interspersed with hydrophobic amino acids. Perhaps this was the voltage sensor? It would mean that S4 would have to sit in the membrane and slide through it in response to voltage change. The few structures available for membrane proteins at the time had shown that membrane segments tended to be α helices oriented perpendicular to the membrane plane. These examples led Catterall, Guy, and Seetharamulu to postulate that the arginine side chains of S4 curl around the helix with the pitch similar to the red stripe on a barbershop pole. This arrangement would then allow S4 to turn in a screw-like motion and permit each arginine to replace its predecessor as the S4 helix traversed the membrane (Catterall, 1986 and Guy and Seetharamulu, 1986). Neuron was born when site-directed mutagenesis and functional analysis promised to nail down the molecular mechanism of voltage sensing. The obvious first thing to try was to neutralize S4 arginines.