Page 11 - CBAC Newsletter 2016

Xenopus oocytes, and neurons (161). Both ligands shift
the voltage dependent activation curve leftward and
slow the deactivation rate. The actions of these ligands
increase KCNQ2/3 currents and hyperpolarize the
resting membrane potential of neurons. Meclofenamic
acid and diclofenac decrease both the evoked and
spontaneous spiking activity of rat cortical neurons.
Animal studies have shown that meclofenamic acid
and diclofenac inhibit the spontaneous neuronal action
potential by improving the M-current (161). Both ligands
are anticonvulsants in mice models, measured by MES
(maximal electroshock-induced seizure) (161).
Fenamate’s effects on potassium channels might be
promising for understanding the mechanism of their
actions on various receptors, and whether some of them
are responsible for many treatment effects and side
effects (100,113,114).
Interesingly, the diphenylamine functional group in
fenamate compounds is fairly similar to the two phenyl
rings in retigabine (Fig.2). Fenamate compounds and
retigabine have two benzene rings linked through one
or two atoms. Retigabine and diclofenac are selective
activators of different KCNQ channels.
While retigabine is a potent activator of KCNQ3
homomeric channels (100), meclofenamic acid is potent
on KCNQ2 homomeric channels. Co-application of
retigabine and meclofenamic acid on KCNQ2/3
channels has displayed additive effects, which suggest
that the two activators may act independently on two
different binding sites of KCNQ2/3 channels (161).
Meclofenamic and diclofenac are selective agents for
KCNQ channels over other delayed rectifier channels, for
instance, Kv1.2, Kv1.5, and Kv2.1 (161).
KCNQ Channel Inhibitors
1. XE991
XE991 is only a moderate inhibitor of almost all sub-
types of KCNQ channels (Fig.3). However, XE991 blocks
KCNQ channels at low µM concentrations, and it affects
other types of potassium channels only at higher mM
concentrations (72,166). XE991 is a tenfold more
potent inhibitor of the KCNQ1 current than of the KCNQ1
+ KCNE1 current. XE991 decreases activation and
deactivation time constants, and shifts the activation
curve o0f.7IK8s channels to more positive voltages
(KD = µM and KD = 11 µM for KwCaNs Qa1lsoanfoduInKsd
channels, respectively) (Table 3). It
the inhibition effect of XE991 is both time and
voltage-dependent with IKs channels (167).
When KCNQ1 and KCNE3 subunits are coexpressed
in Xenopus oocytes, XE991blocks the heteromeric
channels more potently than KCNQ1 channels. The
inhibition effect of XE991 on epithelial chloride transport
is evidence for the blocking effect of this ligand on
KCNQ1 + KCNE3 heteromeric channels (168). Thus, the
selectivity of XE991 is dependent on the composition of
accessory subunits in association with the KCNQ
subunits in different channels complexes.
XE991 can evoke contraction of arteries and
depolarization of smooth muscles in rodents and
humans (169-172). Constriction of the intrapulmonary
arteries of rats and mice (IPA) by XE991 is also evidence
for functional KCNQ channels in modulating vascular
vasoconstriction (173).
XE991 acts as a cognitive enhancer by releasing
stimulant-evoked transmitter from the central nervous
system (174). It is believed that the effect of XE991 is
the results of inhibition of M-current (12,175). The
inhibition effect of XE991 on KCNQ channels may be
part of the resting conductance of the parasitophorous
vacuole membrane (PVM). The ligand has also shown
the ability to enhance portal vein excitability (176).
2. Linopirdine
Like its analogue XE991, linopirdine is a potent KCNQ
channel inhibitor (Fig.3). At concentrations of a few
µM, linopirdine inhibits almost all subtypes of KCNQ
channels; nevertheless, its effects on other potassium
channels have been noticed only at mM concentrations
(10,72,166,177). Linopirdine can block heterologous
KCNQ channels with different potencies, according to
the assembled subunits.
Native PVM (portal vein myocytes) delayed-rectifier
potassium currents were inhibited by linopirdine. In the
presence of linopirdine, both the amplitude and duration
of evoked depolarization in PVM were enhanced, giving
the first evidence for functional KCNQ channels in
vascular myocytes and a role of KCNQ channels in VSMC
(vascular smooth muscle cell) repolarization (178).
Linopirdine stimulates membrane depolarization and
also induce excitability of isolated portal veins (176).
Linopirdine constricts the intrapulmonary arteries (IPA)
of an endothelium and nerve terminal in the vessel wall
from rat and mouse models at IC50 = 1 μM, predicting a
role for KCNQ in regulating vasoconstriction. The effect
of linopirdine is eliminated in the presence of nifedipine,
that
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