The three topics chosen for discussion by the organizers of this meeting are (1) the structural basis of function of hERG channels, (2) the physiological roles of hERG channels and (3) mechanisms of drug-induced long QT syndrome (LQTS). Due to time constraints, we will not have formal presentations on many other important topics related to hERG biology, but we plan to address some of these issues during the discussion periods. Although an X-ray crystallographic structure is not available for hERG, we do have a model that is based on crystal structures of the bacterial channels KcsA, KvAP and MthK (Doyle et al 1998, Jiang et al 2002, 2003). We know from biophysical studies of Shaker and the X-ray structures of these bacterial channels that the S5, pore helix and S6 transmembrane domains compose the pore domain of hERG, as well as the likely structural basis of the selectivity filter. The S1-S4 transmembrane domains comprise the voltage-sensing component of the channel. The fourth transmembrane domain is by far the most important part of the voltage sensor, with several positively charged amino acids spaced three residues apart. Some of the basic residues in S4 also interact with the few acidic residues located in the S2 and S3 transmembrane domains. What is unusual about hERG is that it activates very slowly and inactivates rapidly compared to most other voltage-gated K~+ channels. The regions thought to be important for slow activation and deactivation include the N-terminal PAS domain, the S4-S5 linker and the end of the S6 domain. The structural basis for rapid inactivation is unknown, but it is presumed to be somewhat similar to C-type inactivation, involving residue interactions between S5 and the pore loop.
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