On the structural basis of modal gating behavior in K+ channels

Abstract

The K+ channels can display three distinct gating modes. The molecular basis for two of these modes (low open probability and flickery) are now examined by a combination of single-channel recording, crystallography and modeling of mutants in Glu71, revealing that changes in ion and water occupancy in and around the selectivity filter determine modal gating. Modal-gating shifts represent an effective regulatory mechanism by which ion channels control the extent and time course of ionic fluxes. Under steady-state conditions, the K+ channel KcsA shows three distinct gating modes, high-Po, low-Po and a high-frequency flicker mode, each with about an order of magnitude difference in their mean open times. Here we show that in the absence of C-type inactivation, mutations at the pore-helix position Glu71 unmask a series of kinetically distinct modes of gating in a side chain–specific way. These gating modes mirror those seen in wild-type channels and suggest that specific interactions in the side chain network surrounding the selectivity filter, in concert with ion occupancy, alter the relative stability of pre-existing conformational states of the pore. The present results highlight the key role of the selectivity filter in regulating modal gating behavior in K+ channels.