TY - JOUR
T1 - Activation of Kv7 (KCNQ) voltage-gated potassium channels by synthetic compounds
AU - Xiong, Qiaojie
AU - Gao, Zhaobing
AU - Wang, Wei
AU - Li, Min
N1 - Funding Information:
We thank M. Sanguinetti, L. Jan and members of the Li laboratory for discussions and comments on the manuscript. This work was supported by grants from the National Institutes of Health (to M.L. GM070959 and GM078579) and a postdoctoral fellowship from American Heart Association (to Z.G. 0725388U).
PY - 2008/2
Y1 - 2008/2
N2 - 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.
AB - 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.
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U2 - 10.1016/j.tips.2007.11.010
DO - 10.1016/j.tips.2007.11.010
M3 - Review article
C2 - 18206251
AN - SCOPUS:38749119750
SN - 0165-6147
VL - 29
SP - 99
EP - 107
JO - Trends in Pharmacological Sciences
JF - Trends in Pharmacological Sciences
IS - 2
ER -