Page 9 - CBAC Newsletter 2016
P. 9
SF0034 may become a potential therapeutic candidate be required.
for encephalopathy because recently it was found that ZnPy causes leftward shift in voltage dependent
the KCNQ2 channels, expressed in neonatal brains are a activation of KCNQ channels, and reduces the
regulator of neuronal excitability. Several genetic deactivation rate. In addition, ZnPy enhances channels
mutations in KCNQ2 potassium channels lead to currents at all physiological voltages (137). Unlike
epileptic encephalopathy in neonatal children and retigabine, which acts mostly by shifting KCNQ voltage
infants (131-134). SF0034 may be a better treatment dependence of activation but has minor potentiation
for children with KCNQ2 encephalopathy than effects at higher saturated voltages, ZnPy enhances
retigabine. KCNQ2/3 channels were also found to be maximum opening probability of KCNQ channels
directly related to tinnitus, and retigabine inhibits (101,117). Also, unlike retigabine, which loses effects
tinnitus development in a mouse (95). Tinnitus is on the W236L mutant KCNQ2, ZnPy is highly effective
experienced by one-eighth of the world’s population in potentiating the mutant channel, indicating that ZnPy
(135), and SF0034 may also become an excellent and RTG do not bind to the same site (137). It was
clinical candidate for treating tinnitus. This ligand is not suggested that the presence of a zinc ion in the
only promising as a new clinical candidate to treat many structure of ZnPy is important for its action in neuronal
forms of epilepsy and tinnitus, but also a powerful functions (Fig 2) (141).
experimental tool to study KCNQ channels.
3. Zinc Pyrithione (ZnPy) Interestingly, ZyPy has been recently demonstrated to
Zinc pyrithione (Fig.2) was found by a relatively new activate KCNQ channels after PIP2 depletion, suggesting
experiment called function recovery after that it competes with PIP2 for the same binding site.
chemobleaching (FRAC) (136). The channels expressed The potentiation effect by ZnPy was reduced when it
on the surface of targeted cells were chemobleached, was tested with channels mutated in the putative PIP2
the replenished channel activity after chemobleaching binding site (142). This finding may suggest that ZnPy
was monitored, and the time for recovery was measured targets the PIP2 binding site, and plays a role in the
by nonradioactive rubidium flux assay. A pulse-chase VSD-PGD coupling. Thus, ZnPy represents a new class
assay monitored function recovery after bleaching with of ligand with a novel mechanism of action (82).
a specific chemical, to determine the time it took for the 4. Flupirtine and N-ethylmaleimide (NEM)
ion channel to reach the cell surface (136). This The centrally acting, non-opioid analgesic flupirtine
experimental combination was first tested to identify is widely used in Europe for the treatment of chronic
inhibitors for hERG and Kir2.1 with mechanism of action pains, such as lower-back pain and cancer-associated
that are either to inhibit channel activity or regulate pain (Fig.2) (143-145). Flupirtine affects the function of
trafficking and half-life of channel proteins. This strategy multiple ion channels and receptors. Although flupirtine
was later used to screen KCNQ channels with many is a neuronal potassium channel opener, it is a NMDA
ligand libraries, searching for a ligand with agonist receptor antagonist and a GABAA receptor modulator
activity (137). (146). The mechanism underlying the clinic effects
Zinc pyrithione (ZnPy) activates KCNQ1 channels of flupiritine has not been fully revealed yet, however
(EC50=3.5 μM), and it also activates other KCNQ some studies have reported that its effects on neuronal
channels, such as KCNQ2, KCNQ4, and KCNQ5 excitability are mainly due to their actions by opening
(Table 1). While ZnPy strongly potentiates M-current of voltage-gated KCNQ channels (147,148). Flupirtine
channels, it has shown no significant effects on has shown neuroprotective roles both in vitro and in vivo
voltage-gated potassium channels other than KCNQ (17,149,150). It may be used to prevent memory and
(138). ZnPy does not show a significant effect on learning problems because it has been reported to treat
KCNQ3 channels, which may suggest that it does not seizures by activating KCNQ channels (151,152).
bind to them (137,139). Flupirtine has been reported to have neuroprotective
ZnPy has shown the ability to manage some genetic effects on spatial memory retrieval and hippocampal
mutations of neonatal epilepsy and myokymia patients long-term potentiation (LPT). Applying acute stress has
(137). For years, ZnPy has been used clinically to treat been noticed to decrease the expression of KCNQ2 and
dandruff and psoriasis (140). However, many studies on 3 channels in the hippocampus, leading to impair the
ZnPy in animal models, its mechanism of actions, and functions of spatial memory retrieval and hippocampal
developing derivatives for clinical studies and uses may LPT. The M-current activator, flupirtine prevent this
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