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Up-Regulation of the Inwardly Rectifying K+ Channel Kir2.1 (KCNJ2) by Protein Kinase B (PKB/Akt) and PIKfyve

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Abstract

The inward rectifier K+ channel Kir2.1 contributes to the maintenance of the resting cell membrane potential in excitable cells. Loss of function mutations of KCNJ2 encoding Kir2.1 result in Andersen-Tawil syndrome, a disorder characterized by periodic paralysis, cardiac arrhythmia, and dysmorphic features. The ubiquitously expressed protein kinase B (PKB/Akt) activates the phosphatidylinositol-3-phosphate-5-kinase PIKfyve, which in turn regulates a variety of carriers and channels. The present study explored whether PKB/PIKfve contributes to the regulation of Kir2.1. To this end, cRNA encoding Kir2.1 was injected into Xenopus oocytes with and without additional injection of cRNA encoding wild type PKB (PKB), constitutively active T308D,S473DPKB or inactive T308A,S473APKB. Kir2.1 activity was determined by two-electrode voltage-clamp. As a result, PKB and T308D,S473DPKB, but not T308A,S473APKB, significantly increased Kir2.1-mediated currents. The effect of PKB was mimicked by coexpression of PIKfyve but not of S318APikfyve lacking the PKB phosphorylation site. The decay of Kir2.1-mediated currents after inhibition of channel insertion into the cell membrane by brefeldin A (5 μM) was similar in oocytes expressing Kir2.1 + PKB or Kir2.1 + PIKfyve to those expressing Kir2.1 alone, suggesting that PKB and PIKfyve influence channel insertion into rather than channel retrieval from the cell membrane. In conclusion, PKB and PIKfyve are novel regulators of Kir2.1.

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Acknowledgments

The authors acknowledge the technical assistance of E. Faber. The article was meticulously prepared by S. Rübe. This study was supported by the Deutsche Forschungsgemeinschaft (GK 1302).

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  1. Department of Physiology, University of Tübingen, Gmelinstr 5, 72076, Tübingen, Germany

    Carlos Munoz, Ahmad Almilaji, Michael Föller & Florian Lang

  2. Department of Physiology, Faculty of Medicine, Universitas Padjadjaran, Banding, Indonesia

    Iwan Setiawan

  3. Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network (UHN), 620 University Avenue, Toronto, ON, M5G 2C1, Canada

    Michael Föller

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  1. Carlos Munoz
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Correspondence to Florian Lang.

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Munoz, C., Almilaji, A., Setiawan, I. et al. Up-Regulation of the Inwardly Rectifying K+ Channel Kir2.1 (KCNJ2) by Protein Kinase B (PKB/Akt) and PIKfyve. J Membrane Biol 246, 189–197 (2013). https://doi.org/10.1007/s00232-012-9520-9

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