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Inhibition of Kir2.1 (KCNJ2) by the AMP-activated protein kinase

Ioana Alesutan1, Carlos Munoz, Mentor Sopjani

  • 1Department of Physiology, University of Tübingen, Gmelinstrasse 5, Tübingen, Germany.

Biochemical and Biophysical Research Communications
|April 20, 2011
PubMed

Insights

The AMP-activated protein kinase (AMPK) regulates the Kir2.1 potassium channel, impacting cell membrane potential. AMPK reduces Kir2.1 activity and cell membrane levels, partly via Nedd4-2 phosphorylation.

Area of Science:

  • Physiology
  • Molecular Biology
  • Biochemistry

Background:

  • The inward rectifier potassium channel Kir2.1 is crucial for maintaining cell membrane potential in neurons and cardiac myocytes.
  • Mutations in KCNJ2, encoding Kir2.1, cause Andersen-Tawil syndrome, characterized by periodic paralysis, cardiac arrhythmia, and skeletal abnormalities.
  • Ischemia decreases cardiac cell membrane potential and activates AMP-activated serine/threonine protein kinase (AMPK), an energy-sensing kinase.

Purpose of the Study:

  • To investigate whether AMPK regulates the function and abundance of the Kir2.1 channel.
  • To explore the molecular mechanisms underlying AMPK's regulation of Kir2.1.

Main Methods:

  • Xenopus oocytes were injected with cRNA encoding Kir2.1, along with various forms of AMPK or the ubiquitin ligase Nedd4-2.
  • Kir2.1 activity was measured using two-electrode voltage-clamp experiments.
  • Kir2.1 protein levels in the cell membrane were quantified via immunostaining and confocal imaging.

Main Results:

  • Both wild-type and constitutively active AMPK significantly decreased Kir2.1-mediated currents and Kir2.1 protein abundance in the cell membrane.
  • Nedd4-2 expression downregulated Kir2.1 currents, an effect potentiated by co-expressed AMPK.
  • Nedd4-2(S795A), a mutant lacking an AMPK phosphorylation site, showed reduced downregulation of Kir2.1 currents compared to wild-type Nedd4-2 when co-expressed with AMPK.

Conclusions:

  • AMPK is a significant regulator of Kir2.1 channel activity and membrane expression.
  • AMPK's regulatory effect on Kir2.1 is, at least partly, mediated through the phosphorylation of the ubiquitin ligase Nedd4-2.

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