Figure 11

A Schematic model illustrating the mechanism underlying Mg²⁺ block of the Kir2.1 channel pore.

(a) The WT Kir2.1 channel comprises cytoplasmic and transmembrane domains. The ion conduction pathway in the transmembrane domain could be further divided into the selectivity filter and the central cavity. SPM probably binds to a blocking site involving D172 with a curly form¹³. Moreover, SPM may go through the selectivity filter of the Kir2.1 channel, entering the extracellular side of the channel if there is a large driving force. (b) With strong outward K⁺ currents, intracellular Mg²⁺ is pushed to the outermost site of the flux–coupling region (probably involving S165) in the Kir2.1 channel pore. Mg²⁺ is more weakly bound to its site than SPM. However, unlike SPM, intracellular Mg²⁺ could not traverse the selectivity filter of Kir2.1 channel pore and exit to the outside even with a large driving force. (c) We illustrate that concomitant intracellular Mg²⁺ and SPM are synergistic in the blocking action of the Kir2.1 channel pore. SPM has a strong flow–dependent movement in the central cavity and thus a strong blocking effect on the outward K⁺ currents when SPM gets “stuck” at the junction between central cavity and selectivity filter. SPM, however, can not completely block the outward K⁺ currents even with highly preponderant outward K⁺ flux (e.g., very strong depolarization) because of the possibility of outward exit of the blocking SPM through the selectivity filter. On the other hand, Mg²⁺ has a much weaker flow–dependent movement in the central cavity and thus millimolar Mg²⁺ has an even weaker overall blocking effect on the outward K⁺ currents than micromolar SPM. Concomitant Mg²⁺ and SPM, however, would have a synergistic rather than additive blocking effect on the outward K⁺ current especially at strong depolarization. This is because the apparently weaker blocker Mg²⁺ could prohibit the outward exit of SPM and thus effectively reduce the residual outward K⁺ currents, either by direct physical hindrance or by the possible narrowing conformational changes at ~D172 residues induced by coexisting Mg²⁺ and SPM (Fig. 10), or by both.