Activation of Kv7 (KCNQ) voltage-gated potassium channels by synthetic compounds.

Qiaojie Xiong, Zhaobing Gao, Wei Wang, Min Li

Department of Neuroscience and High Throughput Biology Center, School of Medicine, Johns Hopkins University, 733 North Broadway, Baltimore, MD 21205, USA.

Trends in pharmacological sciences 2008 Feb

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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.

Citation

Qiaojie Xiong, Zhaobing Gao, Wei Wang, Min Li. Activation of Kv7 (KCNQ) voltage-gated potassium channels by synthetic compounds. Trends in pharmacological sciences. 2008 Feb;29(2):99-107