Referenced in: none

Automatically associated channels: Kv7.1

Title: Regulation of wild-type and mutant KCNQ1/KCNE1 channels by tyrosine kinase.

Authors: Sergey Missan, Jiansong Qi, Julie Crack, Terence F McDonald, Paul Linsdell

Journal, date & volume: Pflugers Arch., 2009 Jul , 458, 471-80

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/19139916

Abstract
The objective of the study was to investigate the role of tyrosine phosphorylation in the regulation of KCNQ1/KCNE1 channels. Large whole-cell time- and voltage-dependent K(+) currents were present in human embryonic kidney 293 cells cotransfected with human KCNQ1 and KCNE1 but not in control nontransfected cells. The time- and voltage-dependent current had biophysical properties typical of cardiac KCNQ1/KCNE1 current and was almost completely abolished by KCNQ1 blocker chromanol 293B (50 microM). Both KCNQ1/KCNE1 and KCNQ1 current were inhibited in a voltage-independent manner by tyrosine kinase (PTK) inhibitor tyrphostin A25 (100 microM), but not by PTK-inactive tyrphostin A1 (100 microM), suggesting involvement of tyrosine phosphorylation in maintaining channel activity. This view was strengthened by the finding that phosphotyrosyl phosphatase inhibitor monoperoxo(picolinato)-oxo-vanadate(V) (200 microM) reversed the inhibition of current by tyrphostin A25. However, the channel-pertinent tyrosine phosphorylation modulated by these compounds does not appear to be on the channel itself because inhibition of current by tyrphostin A25 was unaffected by single and multiple mutations of KCNQ1 cytoplasmically accessible tyrosine residues. Inhibition by tyrphostin A25 was unaffected by intracellularly applied diC8 phosphatidylinositol-4,5-bisphosphate (diC8 PIP(2); 25 microM), and based on the results obtained from cell surface biotinylation experiments, it was not due to loss of channels from the membrane. We conclude that tyrphostin A25 inhibits KCNQ1/KCNE1 current by lowering tyrosine phosphorylation on unidentified nonchannel protein(s) that directly or indirectly regulate the open probability of the KCNQ1 pore in a PIP(2)-independent manner.