Merging Shaker K+ channel electrophysiology with structural data by a nucleation and growth mechanism

Abstract

The ON and OFF ionic and gating currents of the Shaker K+ channel were simulated with a kinetic model that predicts stepwise outward movement and aggregation of the four subunits of its tetrameric structure during depolarization, followed by their downward movement and disaggregation during repolarization. Only a maximum of three free parameters is required for the simulation. The model provides explanations for the Cole-Moore effect, the rising phase of the ON gating current and the long-term (C-type) inactivation of the OFF gating current, with gating charge immobilization. The latter phenomenon is explained by a gradual strengthening of the interaction between the ball-and-chain blocker and its receptor just below the selectivity filter. This strengthening, which stems from conformational changes around the outer mouth of the pore, determines a slow release of the gating charge during repolarization. By merging the model predictions based on the interpretation of electrophysiological data with the available structural data, a detailed description of the consecutive series (C/O)→(O/O)→(O/I)→(C/I) of channel states is proposed, where the first letter refers to the closed (C) or open (O) activation gate, and the second to the open (O) or inactivated (I) selectivity filter. The role of electrostatic attractions within the channel is emphasized.