hERG Potassium Channels in Drug Discovery and Development - Ion Channels and Their Inhibitors - page 158

amino acid- and domain-related success and failure of chemical chaperones.
Finally, the high concentrations of chemical chaperones required for restoration
of protein trafficking (e.g., 10% glycerol) restrict their clinical use [ 33 , 34 ]. In
another sense, trafficking of mutant G601S and F805C channels was restored by
application of sarcoplasmic/ER Ca 2+ -ATPase (SERCA) inhibitor thapsigargin,
which did not cause hERG current inhibition. It is speculated that in this
mechanistically different case, alterations in the activity of calcium-dependent
chaperone proteins in the ER promote the relocation of intracellular hERG protein
to the cell surface. The underlying mechanism requires an intact Golgi apparatus.
Further studies are required to investigate the precise mechanism of rescue by
thapsigargin and to identify the chaperones involved in this rescue pathway [ 35 ].
Pharmacological rescue of trafficking-deficient hERG mutants appears to be the
most promising approach. It has been revealed that trafficking of some Class 4
hERG mutants (e.g., hERG T65P, hERG N470D, hERG G601S) can be restored by
application of high-affinity hERG channel ligands (i.e., inhibitors) such as
methanesulfonanilide, and E4031, antihistamines agents such as astemizole and
terfenadine, or gastrointestinal prokinetic drug such as cisapride. In contrast,
attempts to rescue mutant hERG A561V, hERG R752W, hERG F805C or hERG
R823W channels by incubation of pharmacological chaperones failed, suggesting
that these channels represent a group of hERG LQT2 mutants, which is resistant to
pharmacological rescue. More recently, the molecular determinants and the binding
site for hERG channel ligand serving as pharmacological chaperones have been
investigated. Nonetheless, pharmacological restoration of hERG channel matura-
tion with high-affinity inhibitors of hERG currents requires application of the drug
to the culture medium for a certain incubation time, followed by removal of the
hERG -blocking drug prior to electrophysiological measurements, which prevents
their clinical use [ 36 - 38 ]. Trafficking defects are present in a significant group of
hERG mutants associated with LQT2. Since many of the trafficking-deficient
channels give rise to functional channels when inserted into the cell membrane,
restoration of normal channel trafficking is an attractive strategy for treating
patients carrying Class 4 hERG mutations [ 39 ]. Among the strategies investigated
to date, pharmacological restoration of hERG maturation with low-affinity channel
antagonists seems to be most promising. However, limitations may derive from the
fact that in each LQTS patient, the underlying mutation needs to be analyzed and
characterized in vitro and the efficacy of specific therapies should be evaluated for
each individual mutation prior to treatment [ 40 - 42 ].
2 QT Interval Prolongation and Torsade De Pointes
Lengthening of ventricular repolarization (Figs. 2 and 3 ) is known to be a risk factor
for development of Tdp , a form of ventricular tachycardia thought to be initiated by
an early after depolarization (EAD). Tdp is a potentially lethal arrhythmia that
develops as a consequence of amplification of electrical heterogeneities intrinsic to