Inhibition of the heterotetrameric K++ channel KCNQ1/KCNE1 by the AMP-activated protein kinase

Author: Alesutan Ioana   Fööller Michael   Sopjani Mentor   Dëërmaku-Sopjani Miribane   Zelenak Christine   Frööhlich Henning   Velic Ana   Fraser Scott   Kemp Bruce E.   Seebohm Guiscard   Vöölkl Harald   Lang Florian  

Publisher: Informa Healthcare

ISSN: 1464-5203

Source: Molecular Membrane Biology, Vol.28, Iss.2, 2011-02, pp. : 79-89

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Abstract

AbstractThe 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 (AMPKαα1 ++ AMPKββ1 ++ AMPKγγ1), of the constitutively active γγR70QAMPK (αα1ββ1γγ1(R70Q)), of the kinase dead mutant ααK45RAMPK (αα1(K45R)ββ1γγ1), 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.

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