hERG Potassium Channels in Drug Discovery and Development - Ion Channels and Their Inhibitors - page 155

channel is a homotetramer having each of its subunit consisting of six transmem-
brane -helices viz. S1-S6 and a pore helix situated between S5 and S6 through

which ion conduction takes place (Fig. 1 ). Voltage sensing domains (VSDs) are
integral components of hERG ion channels. The S1-S4 transmembrane domains
from each subunit form the VSD, which move within the membrane in response to
transmembrane voltage and regulate opening and closing of pore of voltage-gated
K + channel [ 9 , 10 ]. Between S5 and S6 helices, there is an extracellular loop
(known as “the turret”) and the pore loop, which begins and ends extracellularly
but loops into the plasma membrane; the pore loop for each hERG subunits in one
channel face into the ion-conducting pore and are adjacent to the corresponding
loops of three other subunits and together they form selectivity filter region of the
channel pore [ 11 ]. In addition to these transmembrane regions, hERG has intracel-
lular N-terminal and C-terminal domains. The N-terminal region contains a
Per-Arnt-Sim (PAS) domain, where they play important role in deactivation of
the channel. The C-terminal tail contains a cyclic nucleotide binding domain
(CNBD) whose function is not well characterized. Binding of cAMP to this
domain has relatively little effect on gating [ 12 ]. However, this region is still an
important consideration with respect to arrhythmogenesis since mutations in this
region have been shown to cause trafficking defects [ 13 , 14 ].

a

1.3 Functions and Dysfunctions of hERG K + Channels

hERG K + channel plays a key role in regulation of cardiac excitability and mainte-
nance of normal cardiac rhythm. One-third of all cases of congenital long QT
syndrome (LQTS) are primarily caused by mutation in hERG . In addition, hERG
channel protein is the molecular target for almost all drugs that cause acquired form
of long QT syndrome. Due to significance of hERG gating kinetics in both normal
and abnormal cardiac function, much of the work has focused on understanding the
voltage-dependent molecular rearrangements of channel protein [ 15 ]. hERG kinetic
is distinct showing slow activation and rapid voltage-dependent inactivation
resulting into outflow of small current through these channels. This is of importance
in maintenance of plateau phase in cardiac action potential. In phase 3, a sharp
outflow of K + current takes place as a result of quick recovery of channels from
inactivated state. The current then decreases slowly until stimulus for second action
potential arrived. Sequence alignments and hydropathy plots recommend that the
overall structure of the VSD is homologous to that of other K v channels, and it is
suggested that S4 helix is loosely packed and most likely lipid exposed, much as it
is presented in the crystal structure of K v 1.2. hERG channel dysfunction arising out
of mutation may have adverse effects on cardiac electrical activity, and therefore its
understanding may be helpful for knowing the correct functioning of K v 11.1 and
designing proper therapy to avoid it. Till date about 300 mutations have been
reported in K v 11.1 channel. Mechanisms of mutations mainly due to reduced or
defective gating or synthesis or trafficking or ion permeation or single channel