Activation of epidermal growth factor receptor inhibits KCNQ2/3 current through two distinct pathways: membrane PtdIns(4,5)P2 hydrolysis and channel phosphorylation.
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.
Jia
Qingzhong
Q
Department of Pharmacology, Hebei Medical University, Shijiazhuang 050017, China.
Jia
Zhanfeng
Z
Zhao
Zhiying
Z
Liu
Boyi
B
Liang
Huiling
H
Zhang
Hailin
H
D000818:Animals; D002478:Cells, Cultured; D004553:Electric Conductivity; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D051658:KCNQ2 Potassium Channel / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology*; D051659:KCNQ3 Potassium Channel / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology*; D007668:Kidney / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D008566:Membranes / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017783:Superior Cervical Ganglion / Q000166:cytology / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D051658:KCNQ2 Potassium Channel; D051659:KCNQ3 Potassium Channel; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates; D014443:Tyrosine; D004815:Epidermal Growth Factor; D066246:ErbB Receptors