hERG Activators

The recent discovery of several structurally diverse hERG activators could be an immense breakthrough in terms of treating clinical conditions with hERG targets, as well as potentially increasing the safety of other drugs known to block hERG.  Recently five hERG activator compounds have been described: RPR260243 [Kang et al., 2005], NS1643 [Hansen et al., 2006a], NS3623 [Hansen et al., 2006b], PD‑118057 [Zhou et al., 2005], and mallotoxin [Zeng et al., 2006].  PD‑118057, NS3623 and RPR260243 have been shown to shorten both the ventricular AP duration and the QT interval.  RPR260243 and PD-118057 can reverse the action potential prolonging effects of dofetilide.  The mechanism of action of these channel activators is varied.  NS1643 and NS3623 primarily reduce the inactivation of hERG by shifting its voltage dependence rightward [Casis et al., 2006; Hansen et al., 2006b]; neither compound was designed to interact with the S5-Pore linker, and their sites of action with the hERG channel are as yet unknown.  Mallotoxin affects all three, strongly shifting the activation curve leftward, but also slowing deactivation and have minor effects on inactivation.  In addition it may be possible to modulate hERG activity with drugs acting on protein kinases, as hERG current can be reduced by protein kinase A (PKA) activity [Thomas et al., 1999; Kiehn et al., 1998], and further research has teased out an indirect role for protein kinase C (PKC) in hERG activity [Thomas et al., 2003].

Compounds Influencing hERG Intracellular Sorting

 One mechanism for the loss of normal channel function in some familial forms of LQTS is defective protein trafficking, which results in the failure of the hERG channel protein to reach the plasma membrane. E-4031, a hERG blocking drug, was found to correct the intracellular sorting of the mutant hERG-N470D protein [Zhou et al., 1999], although the E-4031 also blocked the channel.  Initially the success of rescue with pharmacological chaperones of hERG-G601S was thought to vary directly with the potency of blockade, and even the molecular determinants for the chaperones were found [Ficker et al., 2002].  However, thapsigargin was shown to rescue the surface expression of two different trafficking mutants of hERG without blocking the channel [Delisle et al., 2003], as was fexofenadine [Rajamani et al., 2002].  Hsp90 and Hsp70 are crucial for the maturation of the wild type hERG protein as well as for the retention of trafficking-deficient hERG mutants [Ficker et al., 2003].  In a recent study of ~25% of the known LQT2 (hERG-associated LQTS) missense mutations, 30 of 34 mutations caused trafficking defects, most of which could be pharmacologically corrected [Anderson et al., 2006].

hERG and Short QT Syndrome

Familial short QT syndrome (SQTS) was identified as a new clinical entity in 2000 [Gussak et al., 2000]; since then families with the condition have been identified in the USA, Italy, Spain, The Netherlands, Germany, France, Finland, Brazil, and Turkey ( The condition presents in patients who have shortened QTc intervals (typically of ~320 ms or less [Bjerregaard et al., 2006]), with episodes of atrial and/or ventricular arrhythmia reported, but in whom no evidence of structural heart disease has been identified [Gussak et al., 2000; Gaita et al., 2003]. SQTS is associated with both atrial and ventricular arrhythmias (including inducible ventricular fibrillation at electrophysiological study) and with sudden death.  Since 2004, it has become clear that SQTS is genetically heterogeneous, with mutations to three cardiac K+ ion channel genes identified in SQTS patients: KCNH2 for SQT1, KCNQ1 for SQT2, KCNJ2 for SQT3 [Brugada et al., 2004; McPate et al., 2006b; Bjerregaard et al., 2006].

The first form of SQTS (SQT1) to be identified (and the form that is most commonly seen in those patients for whom genotyping has been conducted) involves a mutation to hERG. The hERG mutation responsible for causing SQT1 is known as N588K (Figure 1), which is an asparagine to lysine mutation located on the extracellular S5-Pore linker of the channel [Brugada et al., 2004]; it has been proposed that inactivation results from the interaction of this part of the channel with residues on the outer pore domain [Clarke et al., 2006].  This mutation has been found in three independent families and has been described genetically as a hotspot for the disorder [Hong et al., 2005].  This mutated channel has attenuated inactivation (the inactivation is shifted rightward by 62 mV at 37ºC), which results in augmented hERG currents that repolarise the ventricular AP early [Cordeiro et al., 2005; McPate et al., 2005].

Figure 1. The Position of the N588K hERG Mutation.

Although the use of implantable cardioverter defibrillators (ICDs) can help protect against the fatal ventricular arrhythmias of SQTS, the tall T-waves characteristic of SQTS can lead to inappropriate shocks due to T-wave over-sensing [Schimpf et al., 2003]; thus, pharmacological adjunct therapies that restore normal QT intervals/T wave morphology would be beneficial. Initial efforts towards pharmacological restoration of QT intervals in SQT1 patients showed that the class III antiarrhythmic sotalol was ineffective at prolonging the QT interval in these patients, while the class I antiarrhythmic quinidine could prolong these shortened QT intervals [Gaita et al., 2004; Brugada et al., 2004].  The N588K mutation has been shown to attenuate significantly sotalol-induced block of hERG channels, whilst attenuating that of quinidine to a lesser extent.

This is concordant with previous data showing that the molecular determinants of hERG blockade for some low affinity blockers (e.g. [Milnes et al., 2003]) may differ from those associated class III antiarrhythmic agents [Mitcheson et al., 2000; Lees-Miller et al., 2000]. Moreover, when comparing those class I to class III antiarrhythmics that have been tested for hERG blockade, the class I antiarrhythmics quinidine [Lees-Miller et al., 2000], disopyramide [Paul et al., 2001] and propafenone [Witchel et al., 2004] can block inactivation-attenuated hERG channels, whereas all of the class III antiarrhythmics had their hERG blockade dramatically attenuated in channels that had reduced inactivation.  Recently McPate et al. suggested that hERG block by the class I antiarrhythmic disopyramide is only slightly attenuated by the N588K mutation, suggesting that it may be worth investigating disopyramide as a clinical adjunct for SQT1 [McPate et al., 2006a].

With SQTS now recognised as a distinct clinical condition, further incidences of individuals with this condition continue to be reported [Hong et al., 2005] (see also:, raising the possibility that in time it may be as common as hereditary long QT syndrome and could provide an explanation for incidences of sudden cardiac death [Gussak and Bjerregaard, 2005].



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