Page 14 - CBAC Newsletter 2016

Ligands that work as activators on KCNQ2/3 or even
KCNQ5, e.g., retigabine and SF0034 are therapeutics
for some forms of epilepsy. Ligands that selectively
inhibit KCNQ2/3 and 5 channels can be potential
cognition enhancers. Ligands that selectivity activate IKs
channels can be promising for the treatment of
arrhythmia, e.g., azimilide and L-7. Another treatment
approach using agents that are selective for potassium
channels may cure dieases associated with genetic
mutations. The discovery of selective agents for specific
homomeric or even heteromeric channels is urgently
needed for better treatments with minimal unwanted
side effects.

These compounds are also used as research tool to Figure 1.
probe the expression of KCNQ channels in various A homology model of KCNQ1 channel based on the
tissues and their physiological roles. Flupirtine and structure of Kv1.2/2.1 chimera and crystal structure
NEM as an example, they induce cell death in of the Kv7.1 proximal C-terminal domain (215,216).
hippocampal cultures, which was inhibited by XE991 A. Enlarged view of a single subunit of KCNQ1 in the
(155). The actions of these ligands are due to their activated state.
effects on KCNQ channel in hippocampal neurons. B. Top view of the overall structure of channel formed
Inhibition of the spontaneous neuronal action potential by a four identical KNCQ1 subunits.
by meclofenamic acid and diclofenac is an evidence for
the action of these ligands in potentiating M-current in
neurons (161).

The availability of specific openers and inhibitors on
KCNQ channels help to confirm the involvement of
KCNQ in many specific disorders, and to help in finding
better treatments for these disorders. Expanding our
knowledge and understanding of KCNQ subunits will
facilitate the discovery of such required selective
inhibitors and openers. Functional and structural
studies of KCNQ channels will improve our
understanding of drug binding and the mode of ligands
actions (e.g. pore blocker, gating modifier, or expression
modulator).

10 | CBAC Center Heartbeat