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The Journal of Neuroscience, January 1, 2003, 23(1):84-95
Subunit-Specific Modulation of KCNQ Potassium Channels by Src Tyrosine Kinase
Nikita Gamper, James D. Stockand, and Mark S. Shapiro Department of Physiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229
We studied regulation by c-Src tyrosine kinase (Src) of KCNQ1-5 channels heterologously expressed in Chinese hamster ovary (CHO) cells and of native M current in rat sympathetic neurons. Using whole-cell patch clamp, we found that Src modulates currents from KCNQ3, KCNQ4, and KCNQ5 homomultimers, KCNQ2/3 heteromultimers and native M current, but not currents from KCNQ1 or KCNQ2 homomultimers. Src overexpression had two effects: a decrease of current amplitude (4- to 15-fold for cloned channels and ~3-fold for M current) and a slowing of activation kinetics by 2-fold. Both Src actions were mostly reversed by bath application of the Src inhibitors erbstatin (20 µM) and PP2 (200 nM), and mimicked by the tyrosine phosphatase inhibitor sodium vanadate (100 µM). Immunoprecipitation and immunoblot analysis showed Src-dependent phosphotyrosine signals associated with KCNQ3, KCNQ4, and KCNQ5 but not with KCNQ1 or KCNQ2 that may be tyrosine phosphorylation of the channel subunits. Expression of a dominant negative Src that cannot phosphorylate substrates had no effect on the current and did not induce phosphotyrosine signals associated with KCNQ3-5 subunits, further indicating that Src actions on KCNQ currents are mediated by tyrosine phosphorylation. Immunostaining and confocal analysis showed no effect of Src overexpression on the abundance of KCNQ3 protein in CHO cells. Finally, experiments using cloned KCNQ2/3 channels, Src and M1 muscarinic receptors, and sympathetic neurons demonstrated that the actions on KCNQ channels by Src and by muscarinic agonists use distinct mechanisms.
Key words: tyrosine kinase; Src; K+ channel; patch-clamp; ion channel modulation; M current; KCNQ channel; signaling; muscarinic receptor
Copyright © 2003 Society for Neuroscience 0270-6474/03/23184-12$05.00/0
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