SUMO modification regulates inactivation of the voltage-gated potassium channel Kv1.5

Mark D. Benson, Qiu Ju Li, Katherine Kieckhafer, David Dudek, Matthew R. Whorton, Roger K. Sunahara, Jorge A. Iñiguez-Lluhí, Jeffrey R. Martens

Research output: Contribution to journalArticle

102 Scopus citations

Abstract

The voltage-gated potassium (Kv) channel Kv1.5 mediates the IKur repolarizing current in human atrial myocytes and regulates vascular tone in multiple peripheral vascular beds. Understanding the complex regulation of Kv1.5 function is of substantial interest because it represents a promising pharmacological target for the treatment of atrial fibrillation and hypoxic pulmonary hypertension. Herein we demonstrate that posttranslational modification of Kv1.5 by small ubiquitin-like modifier (SUMO) proteins modulates Kv1.5 function. We have identified two membrane-proximal and highly conserved cytoplasmic sequences in Kv1.5 that conform to established SUMO modification sites in transcription factors. We find that Kv1.5 interacts specifically with the SUMO-conjugating enzyme Ubc9 and is a target for modification by SUMO-1, -2, and -3 in vivo. In addition, purified recombinant Kv1.5 serves as a substrate in a minimal in vitro reconstituted SUMOylation reaction. The SUMO-specific proteases SENP2 and Ulp1 efficiently deconjugate SUMO from Kv1.5 in vivo and in vitro, and disruption of the two identified target motifs results in a loss of the major SUMO-conjugated forms of Kv1.5. In whole-cell patch-clamp electrophysiological studies, loss of Kv1.5 SUMOylation, by either disruption of the conjugation sites or expression of the SUMO protease SENP2, leads to a selective ≈15-mV hyperpolarizing shift in the voltage dependence of steady-state inactivation. Reversible control of voltage-sensitive channels through SUMOylation constitutes a unique and likely widespread mechanism for adaptive tuning of the electrical excitability of cells.

Original languageEnglish (US)
Pages (from-to)1805-1810
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number6
DOIs
StatePublished - Feb 6 2007

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Keywords

  • Electrical excitability
  • Posttranslational modification
  • Transmembrane protein
  • Ubiquitin-like modifier

ASJC Scopus subject areas

  • General

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