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MOLECULAR AND GENOMIC |
-helix charge mutants on inactivation of hERG K+ channels
1 Department of Medicine, University of New South Wales, St Vincent's Clinical School, Victoria Street, Darlinghurst, NSW 2010, Australia
2 Victor Chang Cardiac Research Institute, Level 9, 384 Victoria Street, Darlinghurst, NSW 2010, Australia
The ether-à-go-go (EAG) family of voltage-gated K+ channels contains three subfamilies, EAG, ether-à-go-go related (ERG) and ether-à-go-go like (ELK). The human ether-à-go-go related gene (hERG) K+ channel has been of significant interest because loss of function in the hERG channel is associated with a markedly increased risk of cardiac arrhythmias. The hERG channel has unusual kinetics with slow activation and deactivation but very rapid and voltage-dependent inactivation. The outer pore region of the hERG K+ channel is predicted to be different from that of other members of the voltage-gated K+ channel family. HERG has a much longer linker between the fifth transmembrane domain (SS) and the pore helix (S5P linker) compared to other families of voltage-gated K+ channels (43 amino acids compared to 14–23 amino acids). Further, the S5P linker contains an amphipathic 
-helix that in hERG channels probably interacts with the mouth of the pore to modulate inactivation. The human EAG and rat ELK2 channels (hEAG and rELK2) show reduced or no inactivation in comparison to hERG channels, yet both channels are predicted to contain a similarly long S5P linker to that of hERG. In this study, we have constructed a series of chimaeric channels consisting of the S1–S6 of hERG but with the S5P -helical region of either hEAG or rELK2, and one consisting of the S1–S6 of rELK2 but with the S5P -helical region of hERG to investigate the role of the S5P linker in inactivation. Our studies show that charged residues on the -helix of the S5P linker contribute significantly to the differences in inactivation characteristics of the EAG family channels. Further, individually mutating each of the hydrophilic residues on the S5P -helix of hERG to a charged residue had significant effects on the voltage dependence of inactivation and the two residues with the greatest affect when mutated to a lysine, N588 and Q592, both lie on the same face of the S5P -helix. We suggest that inactivation of hERG involves the interaction of this face of the S5P -helix with a charged residue on the remainder of the outer pore domain of the channel.
(Received 25 February 2006;
accepted after revision 21 March 2006;
first published online 23 March 2006)
Corresponding author J. Vandenberg: Electrophysiology and Biophysics Program, Victor Chang Cardiac Research Institute, Level 9, 384 Victoria Street, Darlinghurst, NSW 2010, Australia. Email: j.vandenberg{at}victorchang.unsw.edu.au
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J. I. Vandenberg, A. P. Hill, T. J. Campbell, and C. E. Clarke Reply from Jamie I. Vandenberg, Adam P. Hill, Terence J. Campbell, Catherine E. Clarke J. Physiol., November 15, 2006; 577(1): 461 - 462. [Full Text] [PDF]
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