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The human voltage-sensitive K channel hERG plays a fundamental role in cardiac action potential repolarization, effectively controlling the QT interval of the electrocardiogram. Inherited loss- or gain-of-function mutations in hERG can result in dangerous \"long\" (LQTS) or \"short\" QT syndromes (SQTS), respectively, and the anomalous susceptibility of hERG to block by a diverse range of drugs underlies an acquired LQTS. A recent open channel cryo-EM structure of hERG should greatly advance understanding of the molecular basis of hERG channelopathies and drug-induced LQTS. Here we describe an update of recent research that addresses the nature of the particular gated state of hERG captured in the new structure, and the insight afforded by the structure into the molecular basis for high affinity drug block of hERG, the binding of hERG activators and the molecular basis of hERG's peculiar gating properties. Interpretation of the pharmacology of natural SQTS mutants in the context of the structure is a promising approach to understanding the molecular basis of hERG inactivation, and the structure suggests how voltage-dependent changes in the membrane domain may be transmitted to an extracellular \"turret\" to effect inactivation through aromatic side chain motifs that are conserved throughout the KCNH family of channels.

The human human ether-à-go-go–related gene (hERG) potassium channel plays a critical role in the repolarization of the cardiac action potential. Changes in hERG channel function underlie long QT syndrome (LQTS) and are associated with cardiac arrhythmias and sudden death. A striking feature of this channel and KCNH channels in general is the presence of an N-terminal Per-Arnt-Sim (PAS) domain. In other proteins, PAS domains bind ligands and modulate effector domains. However, the PAS domains of KCNH channels are orphan receptors. We have uncovered a family of positive modulators of hERG that specifically bind to the PAS domain. We generated two single-chain variable fragments (scFvs) that recognize different epitopes on the PAS domain. Both antibodies increase the rate of deactivation but have different effects on channel activation and inactivation. Importantly, we show that both antibodies, on binding to the PAS domain, increase the total amount of current that permeates the channel during a ventricular action potential and significantly reduce the action potential duration recorded in human cardiomyocytes. Overall, these molecules constitute a previously unidentified class of positive modulators and establish that allosteric modulation of hERG channel function through ligand binding to the PAS domain can be attained.

The potassium channel protein KCNH2 is encoded by KCNH2 gene, and there are more than 300 mutations of KCNH2. Unfolded protein response (UPR) is typically initiated in response to an accumulation of unfolded and/or misfolded proteins in the endoplasmic reticulum (ER). The present study aimed to explore the UPR process and the role of activating transcription factor 6 (ATF6) in the abnormal expression of potassium voltage-gated channel subfamily H member 2 (KCNH2)A561V. The wild-type (wt) KCNH2 and A561V mutant KCNH2 was constructed with his-tag. The 293 cells were used and divided into KCNH2wt+KCNH2A561V, KCNH2wt and KCNH2A561V groups. The expression levels of ATF6 and KCNH2 in different groups were detected by Western blotting, reverse transcription-quantitative PCR, immunofluo-rescence and immuno-coprecipitation assays. The protein types and abundance of immuno-coprecipitation samples were analyzed by mass spectrometry. The proteomic analysis of the mass spectrometry results was carried out by using the reactome database and GO (Gene Ontology) tool. The mRNA expression levels of KCNH2 and ATF6 in the KCNH2wt+KCNH2A561V group were higher compared with the KCNH2A561V group. However, the full-length protein expression of ATF6 was inhibited, indicating that ATF6 was highly activated and a substantial number of ATF6 was sheared in KCNH2wt+KCNH2A561V group compared with control group. Furthermore, A561V-KCNH2 mutation leading to the accumulation of the immature form of KCNH2 (135 kDa bands) in ER, resulting in the reduction of the ratio of 155 kDa/135 kDa. In addition, the abundance of UPR-related proteins in the KCNH2A561V group was higher compared with the KCNH2wt+KCNH2A561V group. The ‘cysteine biosynthetic activity’ of GO:0019344 process and the ‘positive regulation of cytoplasmic translation activity’ of GO:2000767 process in the KCNH2A561V group were higher compared with the KCNH2wt+KCNH2A561V group. Hence, co-expression of wild-type and A561V mutant KCNH2 in 293 cells activated the UPR process, which led to the inhibition of protein translation and synthesis, in turn inhibiting the expression of KCNH2. These results provided a theoretical basis for clinical treatment of Long QT syndrome.

The KCNH family of ion channels plays important roles in heart and nerve cells. The C-terminal region of the KCNH channel contains a cyclic-nucleotide binding homology domain (CNBHD) which is important for channel gating through interaction with the eag domain. To study the solution structure of CNBHD of the KCNH channel of zebrafish, we over-expressed and purified this domain from E. coli. We report the resonance assignments of the CNBHD. The assignments will allow us to perform structural and dynamic studies for this domain, which will shed light on its role in channel gating.

Long QT syndrome (LQTS) is a condition characterized by prolongation of ventricular repolarization and is manifested clinically by lengthening of the QT interval on the surface ECG. Whereas inherited forms of LQTS associated with mutations in the genes that encode ion channel proteins are identified only in humans, the acquired form of LQTS occurs in humans and companion animal species. Often, acquired LQTS is associated with drug-induced block of the cardiac K(+) current designated I(Kr). However, not all drugs that induce potentially fatal ventricular arrhythmias antagonize I(Kr), and not all drugs that block I(Kr) are associated with ventricular arrhythmias. In clinical practice, the extent of QT interval prolongation and risk of ventricular arrhythmia associated with antagonism of I(Kr) are modulated by pharmacokinetic and pharmacodynamic variables. Veterinarians can influence some of the potential risk factors (eg, drug dosage, route of drug administration, presence or absence of concurrent drug therapy, and patient electrolyte status) but not all (eg, patient gender/genetic background). Veterinarians need to be aware of the potential for acquired LQTS during therapy with drugs identified as blockers of HERG channels and I(Kr).