Referenced in: none

Automatically associated channels: Kv11.1

Title: Proton block of the pore underlies the inhibition of hERG cardiac K+ channels during acidosis.

Authors: Aaron C Van Slyke, Yen May Cheng, Pouya Mafi, Charlene R Allard, Christina M Hull, Yu Patrick Shi, Tom W Claydon

Journal, date & volume: Am. J. Physiol., Cell Physiol., 2012 Jun , 302, C1797-806

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/22517356

Abstract
Human ether-a-go-go-related gene (hERG) potassium channels are critical determinants of cardiac repolarization. Loss of function of hERG channels is associated with Long QT Syndrome, arrhythmia, and sudden death. Acidosis occurring as a result of myocardial ischemia inhibits hERG channel function and may cause a predisposition to arrhythmias. Acidic pH inhibits hERG channel maximal conductance and accelerates deactivation, likely by different mechanisms. The mechanism underlying the loss of conductance has not been demonstrated and is the focus of the present study. The data presented demonstrate that, unlike in other voltage-gated potassium (Kv) channels, substitution of individual histidine residues did not abolish the pH dependence of hERG channel conductance. Abolition of inactivation, by the mutation S620T, also did not affect the proton sensitivity of channel conductance. Instead, voltage-dependent channel inhibition (δ = 0.18) indicative of pore block was observed. Consistent with a fast block of the pore, hERG S620T single channel data showed an apparent reduction of the single channel current amplitude at low pH. Furthermore, the effect of protons was relieved by elevating external K(+) or Na(+) and could be modified by charge introduction within the outer pore. Taken together, these data strongly suggest that extracellular protons inhibit hERG maximal conductance by blocking the external channel pore.