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Inhibition of the heterotetrameric K+ channel KCNQ1/KCNE1 by the AMP-activated protein kinase
Alesultan, Ioana Foller, Michael Sopjani, Mentor Dermaku-Sopjani, Miribane Zelenak, Christine Frohlich, Henning Velic, Ana Fraser, Scott Kemp, Bruce Seebohm, Guiscard
Alesultan, Ioana
Foller, Michael
Sopjani, Mentor
Dermaku-Sopjani, Miribane
Zelenak, Christine
Frohlich, Henning
Velic, Ana
Fraser, Scott
Kemp, Bruce
Seebohm, Guiscard
Abstract
The heterotetrameric K+-channel KCNQ1/KCNE1 is expressed in heart, skeletal muscle, liver and several epithelia including the renal proximal tubule. In the heart, it contributes to the repolarization of cardiomyocytes. The repolarization is impaired in ischemia. Ischemia stimulates the AMP-activated protein kinase (AMPK), a serine/threonine kinase, sensing energy depletion and stimulating several cellular mechanisms to enhance energy production and to limit energy utilization. AMPK has previously been shown to downregulate the epithelial Na+ channel ENaC, an effect mediated by the ubiquitin ligase Nedd4-2. The present study explored whether AMPK regulates KCNQ1/KCNE1. To this end, cRNA encoding KCNQ1/KCNE1 was injected into Xenopus oocytes with and without additional injection of wild type AMPK (AMPKα1 + AMPKβ1 + AMPKγ1), of the constitutively active γR70QAMPK (α1β1γ1(R70Q)), of the kinase dead mutant αK45RAMPK (α1(K45R)β1γ1), or of the ubiquitin ligase Nedd4-2. KCNQ1/KCNE1 activity was determined in two electrode voltage clamp experiments. Moreover, KCNQ1 abundance in the cell membrane was determined by immunostaining and subsequent confocal imaging. As a result, wild type and constitutively active AMPK significantly reduced KCNQ1/KCNE1-mediated currents and reduced KCNQ1 abundance in the cell membrane. Similarly, Nedd4-2 decreased KCNQ1/KCNE1-mediated currents and KCNQ1 protein abundance in the cell membrane. Activation of AMPK in isolated perfused proximal renal tubules by AICAR (10 mM) was followed by significant depolarization. In conclusion, AMPK is a potent regulator of KCNQ1/KCNE1.
Keywords
Date
2011
Type
Journal article
Journal
Molecular Membrane Biology
Book
Volume
28
Issue
2
Page Range
79-89
Article Number
ACU Department
Faculty of Health Sciences
Collections
Relation URI
Source URL
Event URL
Open Access Status
License
File Access
Controlled