hERG Potassium Channels in Drug Discovery and Development - Ion Channels and Their Inhibitors - page 153

heteromultimerize relatively freely, resulting in a wide range of possible channel
tetramers with different biophysical and pharmacological properties. The properties
of K v channel -subunit complexes can be further modified by association with

a

-subunits. As voltage-gated K + channels play important parts in defin-
ing the action potential waveform, modulators of these channels are expected to have
therapeutic utility. Under conditions in which action potential firing is decreased
(specifically, in depression and cognitive dysfunction), K v channel blockers should
restore normal firing. By contrast, K v channel activators should be useful to reduce
pathological hyperexcitability (specifically, in epilepsy and pain) by reducing action
potential firing. In addition to this “mixing and matching” of

intracellular b

-subunits,
K v channel properties can be further modified by phosphorylation, dephosphorylation,
ubiquitylation, and palmitoylation [ 3 ]. Although a number of K + channels contribute
to the process of action potential in cardiac tissue, voltage-gated K + channels 7.1
(commonly known as K v 7.1 or KCNQ1) and K v 11.1 (commonly known as hERG and
KCNH2) play important role in cardiac repolarization, especially in the later phases of
the action potential owing to its unique kinetics ( Flowchart ).

-and

a b

1.1 hERG K + Channels

Upon depolarization, in the ascending phase of the action potential, K v 11.1 opens
rapidly, but K + flux is quickly terminated by channel inactivation. Following
repolarization, release of inactivation is fast and is followed by slow deactivation.
In this way, the channel is active during the depolarization of the action potential
and during part of the diastolic phase of the cardiac cycle. In the later phase,
membrane potential is set at values at which driving force for K + flux is low, but
K + conductance buffers incoming depolarizations [ 4 , 5 ]. Therefore, K v 11.1 has
a pivotal role in setting the duration of effective refractory period of cardiac
action potential. Mutations in K v 11.1 can cause LQTS type 2 because deficient
K v 11.1 function reduces repolarization and increases the possibility of torsades
de pointes ( Tdp ), ventricular fibrillation and sudden death. The considerable interest
of pharmaceutical industry in K v 11.1 is due to the involvement of this channel
in drug-induced or acquired LQTS [ 6 , 7 ]. The hERG inhibitors which inhibit
the hERG channels includes astemizole, dofetilide and imipramine, while some
of the hERG activators which activate hERG channel include NS1643, NS3623,
PD307243, A935142 and RPR26024 [ 8 ].

1.2 Structure of hERG K + Channels

A detailed crystal structure for hERG K + channel is not yet available, so structural
details for this channel are based on analogy with other ion channels, computer
models, and pharmacology and mutagenesis studies. Fundamentally, hERG K +