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Regulation of the Kv2.1 Potassium Channel by MinK and MiRP1

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Abstract

Kv2.1 is a voltage-gated potassium (Kv) channel α-subunit expressed in mammalian heart and brain. MinK-related peptides (MiRPs), encoded by KCNE genes, are single–transmembrane domain ancillary subunits that form complexes with Kv channel α-subunits to modify their function. Mutations in human MinK (KCNE1) and MiRP1 (KCNE2) are associated with inherited and acquired forms of long QT syndrome (LQTS). Here, coimmunoprecipitations from rat heart tissue suggested that both MinK and MiRP1 form native cardiac complexes with Kv2.1. In whole-cell voltage-clamp studies of subunits expressed in CHO cells, rat MinK and MiRP1 reduced Kv2.1 current density three- and twofold, respectively; slowed Kv2.1 activation (at +60 mV) two- and threefold, respectively; and slowed Kv2.1 deactivation less than twofold. Human MinK slowed Kv2.1 activation 25%, while human MiRP1 slowed Kv2.1 activation and deactivation twofold. Inherited mutations in human MinK and MiRP1, previously associated with LQTS, were also evaluated. D76N–MinK and S74L–MinK reduced Kv2.1 current density (threefold and 40%, respectively) and slowed deactivation (60% and 80%, respectively). Compared to wild-type human MiRP1–Kv2.1 complexes, channels formed with M54T– or I57T–MiRP1 showed greatly slowed activation (tenfold and fivefold, respectively). The data broaden the potential roles of MinK and MiRP1 in cardiac physiology and support the possibility that inherited mutations in either subunit could contribute to cardiac arrhythmia by multiple mechanisms.

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Abbreviations

ERG:

ether-a-go-go related gene product

Kv channel:

Voltage-gated potassium channel

MiRP:

MinK-related peptide

TEA:

Tetraethylammonium

TM:

Transmembrane

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Acknowledgements

G. W. A. is grateful for support from the National Institutes of Health (R01 HL079275) and the American Heart Association (grant-in-aid 0855756D). We thank Dr. Sandra Chaplan for assistance with antibody development, Stephanie Backovic for help with protein immunochemistry and Dr. Daniel J. Lerner for insightful comments on the manuscript.

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  1. Torsten K. Roepke

    Present address: Charite Campus Berlin-Buch, Experimental and Clinical Research Center, Franz Volhard Clinic and HELIOS Klinikum, Berlin-Buch, Berlin, Germany

Authors and Affiliations

  1. Greenberg Division of Cardiology, Departments of Medicine and Pharmacology, Weill Medical College of Cornell University, Starr 463, 1300 York Avenue, 10065, New York, NY, USA

    Zoe A. McCrossan, Torsten K. Roepke, Anthony Lewis, Gianina Panaghie & Geoffrey W. Abbott

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  1. Zoe A. McCrossan
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  2. Torsten K. Roepke
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Correspondence to Geoffrey W. Abbott.

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Z. A. McCrossan and T. K. Roepke have contributed equally to this work.

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McCrossan, Z.A., Roepke, T.K., Lewis, A. et al. Regulation of the Kv2.1 Potassium Channel by MinK and MiRP1. J Membrane Biol 228, 1–14 (2009). https://doi.org/10.1007/s00232-009-9154-8

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