Page 5 - CBAC Newsletter 2016

Pharmacology of KCNQ potassium
channels: ligands & drugs

By Moawiah M. Naffaa & Jianmin Cui

Department of Biomedical Engineering
Center for the Investigation of Membrane Excitability Diseases
Cardiac Bioelectricity and Arrhythmia Center, Washington University in St. Louis, St. Louis, MO

Abstract
KCNQ potassium channels are diversely distributed in human tissues, associated with many physiological processes and
pathophysiological conditions. These channels are increasingly used as drug targets for treating diseases. More selective and
potent reagents on various types of KCNQ channels are desirable for appropriate therapies. The recent knowledge of structure
and function of KCNQ channels makes it more feasible to achieve these goals. In this article, we review the structure and
function of KCNQ potassium channels, and some existing compounds that either activate or inhibit KCNQ channels' functions.
We focus on the effects of these compounds on KCNQ channels' functions, their selectivity on various KCNQ channels, their
mechanism of interactions with the channels, and their use either as research tools or as therapeutic agents.

Introduction afterdepolarization in hippocampal neurons (14-20).
KCNQ potassium channels control the electrical KCNQ channels are involved in a wide spectrum of
excitability of neuronal, cardiac muscle, and smooth physiological functions, such as rate adaptation of the
muscle cells, as well as ion transport in epithelia heart during adrenergic stimulation (21), hearing (22),
(1-3). There are five genes encoding the KCNQ subunits pain sensing (23,24), learning, memory, and synaptic
(KCNQ1-5) that are identified by molecular cloning and plasticity (15,25-27).
recombinant expression (4-8). KCNQ subunits form
homotetrimer and heterotetrimer channels that are The KCNQ subunit contains six transmembrane
expressed in various tissues. KCNQ1 homomeric segments, S1-S6. S1-S4 serve as the voltage sensor
channels are mainly expressed in the heart, smooth domain (VSD), and S5-S6 are the pore-gate domain
muscle, and epithelia, where auxiliary subunits from the (PGD) (Fig.1). The N- and the long C-terminal
KCNE family associate with the channel to modify the intracellular domains contain sites that are regulated by
channel properties (9). KCNQ 2-5 channels are mainly intracellular signaling molecules (28-30). The KCNQ1-5
expressed in the nervous system (2,6,7,10-13). KCNQ genes share between 30-65% amino acid identities,
channels have slowly activating and slowly deactivating with the highest similarity in the transmembrane regions
kinetics, and open at voltages close to the resting (7,31). The S4 transmembrane segment, like in other
membrane potential, and the K+ currents persist with voltage gated channels, contains positively charged
prolonged membrane depolarization. These special residues that sense changes of the membrane voltage
characteristics of potassium channels enable them to and move across the membrane to activate the channel.
take part in regulating cardiac and neuronal The loop between S5 and S6 contains the K+ selectivity
excitabilities, which are responsible for action potential filter with the signature sequence TxxTxGYG. Generally,
termination in the heart and enhancing the threshold all KCNQ subunits are homologous in their intracellular
for action potential firing in the nervous system. They N- and C-terminus regions (32,33). However, their
have roles in hippocampal theta oscillation by facilitate C-terminus is variable in length, with KCNQ5 being the
neuronal resonance and network oscillations in cortical longest, and KCNQ1 being the shortest. The number of
neuron (14,15). M-channels also regulate release of amino acids in different subunits varies from 676 in
transmitters, and control spike generation and
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