Article abstract

Nature Chemical Biology 3, 287 - 296 (2007)
Published online: 15 April 2007 | doi:10.1038/nchembio874

Zinc pyrithione-mediated activation of voltage-gated KCNQ potassium channels rescues epileptogenic mutants

Qiaojie Xiong1, Haiyan Sun1 & Min Li1

KCNQ potassium channels are activated by changes in transmembrane voltage and play an important role in controlling electrical excitability. Human mutations of KCNQ2 and KCNQ3 potassium channel genes result in reduction or loss of channel activity and cause benign familial neonatal convulsions (BFNCs). Thus, small molecules capable of augmenting KCNQ currents are essential both for understanding the mechanism of channel activity and for developing therapeutics. We performed a high-throughput screen in search for agonistic compounds potentiating KCNQ potassium channels. Here we report identification of a new opener, zinc pyrithione (1), which activates both recombinant and native KCNQ M currents. Interactions with the channel protein cause an increase of single-channel open probability that could fully account for the overall conductance increase. Separate point mutations have been identified that either shift the concentration dependence or affect potentiation efficacy, thereby providing evidence for residues influencing ligand binding and downstream events. Furthermore, zinc pyrithione is capable of rescuing the mutant channels causal to BFNCs.

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

Correspondence to: Min Li1 e-mail: minli@jhmi.edu