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The Journal of Neuroscience, March 7, 2007, 27(10):2503-2512; doi:10.1523/JNEUROSCI.2911-06.2007

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Cellular/Molecular
Activation of Epidermal Growth Factor Receptor Inhibits KCNQ2/3 Current through Two Distinct Pathways: Membrane PtdIns(4,5)P₂ Hydrolysis and Channel Phosphorylation

Qingzhong Jia, ^* Zhanfeng Jia, ^* Zhiying Zhao, Boyi Liu, Huiling Liang, and Hailin Zhang

Department of Pharmacology, Hebei Medical University, Shijiazhuang 050017, China

Correspondence should be addressed to Hailin Zhang, Department of Pharmacology, Hebei Medical University, 361 Zhongshan East Road, Shijiazhuang, Hebei 050017, China. Email: zhanghl{at}hebmu.edu.cn

KCNQ2/3 currents are the molecular basis of the neuronal M currents that play a critical role in neuron excitability. Many neurotransmitters modulate M/KCNQ currents through their G-protein-coupled receptors. Membrane PtdIns(4,5)P₂ hydrolysis and channel phosphorylation are two mechanisms that have been proposed for modulation of KCNQ2/3 currents. In this study, we studied regulation of KCNQ2/3 currents by the epidermal growth factor (EGF) receptor, a member of another family of membrane receptors, receptor tyrosine kinases. We demonstrate here that EGF induces biphasic inhibition of KCNQ2/3 currents in human embryonic kidney 293 cells and in rat superior cervical ganglia neurons, an initial fast inhibition and a later slow inhibition. Additional studies indicate that the early and late inhibitions resulted from PtdIns(4,5)P₂ hydrolysis and tyrosine phosphorylation, respectively. We further demonstrate that these two processes are mutually dependent. This study indicates that EGF is a potent modulator of M/KCNQ currents and provides a new dimension to the understanding of the modulation of these channels.

Key words: M current; KCNQ current; EGF receptor; modulation; PIP₂; phosphorylation

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Received July 10, 2006; revised Dec. 12, 2006; accepted Dec. 13, 2006.

Correspondence should be addressed to Hailin Zhang, Department of Pharmacology, Hebei Medical University, 361 Zhongshan East Road, Shijiazhuang, Hebei 050017, China. Email: zhanghl{at}hebmu.edu.cn

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