Ion Transport from Physics to Physiology: the Missing Rungs in the Ladder
Activation Gating at the Selectivity Filter in K+ ChannelsCrina Nimigean
Potassium channels are opened by ligands and/or membrane potential. In voltage-gated K+ channels and the prokaryotic KcsA channel, conduction is believed to result from opening of an intracellular constriction that prevents ion entry into the channel. On the other hand, numerous ligand-gated K+ channels may open by a smaller change within the selectivity filter, a narrow region at the extracellular side of the pore. We investigated the location of the gates in the prokaryotic Ca2+-activated K+ channel MthK, homolog with eukaryotic BK channels, and we found that both the voltage and the Ca2+ gates are located within the selectivity filter. In both cases, closure of the MthK pore at the selectivity filter is accompanied by a coupled movement of the pore-lining helices, similar to the movement undergone by the pore-lining helices in K+ channels proposed to gate at the bundle crossing, albeit in the MthK case, the helices do not approach each other enough to form a steric barrier. We then used X-ray crystallography and molecular dynamics simulations to understand the conformational changes undergone at the filter to close the channel. Next, we asked the question whether the selectivity filter may be a universal gate for K+ channels and revisited the location of the gate in KcsA channels. Using molecular dynamics simulations and electrophysiology, we found that ligand-induced conformational changes at the intracellular KcsA entryway had the effect of removing steric restraints at the selectivity filter, thus resulting in structural fluctuations, reduced K+ affinity, and increased ion permeation at this location. Such activation of the selectivity filter may be the universal gating mechanism within K+ channels.