Activation of Kv7 (KCNQ) voltage-gated potassium channels by synthetic compounds.
Voltage-gated Kv7 (or KCNQ) channels play a pivotal role in controlling membrane excitability. Like typical voltage-gated ion channels, Kv7 channels undergo a closed-to-open transition by sensing changes in transmembrane potential, and thereby mediate inhibitory K(+) currents to reduce membrane excitability. Reduction of Kv7 channel activity as a result of genetic mutation is responsible for various human diseases due to membrane hyperexcitability, including epilepsy, arrhythmia and deafness. As a result, the discovery of small compounds that activate voltage-gated ion channels is an important strategy for clinical intervention in such disorders. Because ligand binding can induce a conformational change leading to subthreshold channel opening, there is considerable interest in understanding the molecular basis of these 'gain-of-function' molecules. Although small-molecule activators of cation channels are rare, several novel compounds that activate Kv7 voltage-gated channels have been identified. Recent advances in defining the activator-binding sites and in understanding their mechanism of action have begun to provide insight into the activation of voltage-gated channels by synthetic compounds.
Xiong
Qiaojie
Q
Department of Neuroscience and High Throughput Biology Center, School of Medicine, Johns Hopkins University, 733 North Broadway, Baltimore, MD 21205, USA.
Gao
Zhaobing
Z
Wang
Wei
W
Li
Min
M
D001665:Binding Sites; D006801:Humans; D051656:KCNQ Potassium Channels / Q000187:drug effects* / Q000378:metabolism*; D008024:Ligands; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009422:Nervous System Diseases / Q000188:drug therapy* / Q000503:physiopathology
D051656:KCNQ Potassium Channels; D008024:Ligands