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Down-Regulation of the Epithelial Na+ Channel ENaC by Janus kinase 2

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Abstract

Janus kinase-2 (JAK2), a signaling molecule mediating effects of various hormones including leptin and growth hormone, has previously been shown to modify the activity of several channels and carriers. Leptin is known to inhibit and growth hormone to stimulate epithelial Na+ transport, effects at least partially involving regulation of the epithelial Na+ channel ENaC. However, no published evidence is available regarding an influence of JAK2 on the activity of the epithelial Na+ channel ENaC. In order to test whether JAK2 participates in the regulation of ENaC, cRNA encoding ENaC was injected into Xenopus oocytes with or without additional injection of cRNA encoding wild type JAK2, gain-of-function V617FJAK2 or inactive K882EJAK2. Moreover, ENaC was expressed with or without the ENaC regulating ubiquitin ligase Nedd4-2 with or without JAK2, V617FJAK2 or K882EJAK2. ENaC was determined from amiloride (50 μM)-sensitive current (I amil) in dual electrode voltage clamp. Moreover, I amil was determined in colonic tissue utilizing Ussing chambers. As a result, the I amil in ENaC-expressing oocytes was significantly decreased following coexpression of JAK2 or V617FJAK2, but not by coexpression of K882EJAK2. Coexpression of JAK2 and Nedd4-2 decreased I amil in ENaC-expressing oocytes to a larger extent than coexpression of Nedd4-2 alone. Exposure of ENaC- and JAK2-expressing oocytes to JAK2 inhibitor AG490 (40 μM) significantly increased I amil. In colonic epithelium, I amil was significantly enhanced by AG490 pretreatment (40 μM, 1 h). In conclusion, JAK2 is a powerful inhibitor of ENaC.

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Acknowledgments

The authors acknowledge the meticulous preparation of the manuscript by Lejla Subasic and technical support by Elfriede Faber. This study was supported by the Deutsche Forschungsgemeinschaft.

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

    Zohreh Hosseinzadeh, Dong Luo, Mentor Sopjani, Shefalee K. Bhavsar & Florian Lang

  2. Faculty of Medicine, University of Prishtina, Str. Bulevardi i Dëshmorëve, 10 000, Prishtina, Kosova

    Mentor Sopjani

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  1. Zohreh Hosseinzadeh
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  2. Dong Luo
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Hosseinzadeh, Z., Luo, D., Sopjani, M. et al. Down-Regulation of the Epithelial Na+ Channel ENaC by Janus kinase 2. J Membrane Biol 247, 331–338 (2014). https://doi.org/10.1007/s00232-014-9636-1

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