Molecular mechanisms underlying gating and pHo modulation of the hERG cardiac K+ channel

hERG encodes a K+ channel that underlies the repolarizing cardiac current IKr. Inherited mutations and/or acidosis, as with myocardial ischemia, disrupt hERG gating and lead to life-threatening arrhythmias. Therefore, understanding the mechanisms that underscore hERG gating and proton modification is crucial. Here, we identify a unique glycine (G546) as being critically involved in the unusually slow gating of hERG channels. We show that G546 provides flexibility to the S4-S5 linker, stabilizing the closed state of WT hERG channels. Also, we demonstrate that low pHo inhibits hERG channel function by two independent mechanisms that are not mediated by native histidines: 1) an acceleration of channel closure due to acceleration of voltage sensor return; 2) a reduction of maximal conductance due to direct block of the pore. These data provide novel insight into the mechanisms underlying hERG’s slow gating and reveal the molecular basis underlying proton modulation as seen with myocardial ischemia.