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First published online 17 February 2009
doi: 10.1242/jcs.036632

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SUMOylation regulates Kv2.1 and modulates pancreatic β-cell excitability

¹ Department of Pharmacology, University of Alberta, Edmonton, Alberta, T6G 2E1 Canada
² The Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, T6G 2E1 Canada

^* Author for correspondence (e-mail: pmacdonald{at}pmcol.ualberta.ca)

Accepted 17 November 2008

Summary

The covalent attachment of small ubiquitin-like modifier (SUMO) proteins regulates protein localization and function. SUMOylation has recently been shown to modulate ion-channel function; however, the extent to which this affects native currents and cellular excitability remains to be determined. The voltage-dependent K⁺ (Kv) channel Kv2.1 regulates pancreatic β-cell excitability and insulin secretion. We found that YFP-tagged SUMO1 (SUMO1-YFP) can be immunoprecipitated with Kv2.1 when these two proteins are coexpressed in HEK 293 cells. Furthermore, direct infusion of recombinant SUMO1 peptide or coexpression of SUMO1-YFP inhibited current through cloned Kv2.1 by 80% and 48%, respectively. Insulin-secreting cells express SUMO variants 1 and 3, and expression of the SUMO1-YFP in human β-cells or insulinoma cells inhibited native Kv currents (by 49% and 33%, respectively). Inhibition of the channel resulted from an acceleration of channel inactivation and an inhibition of recovery from inactivation, resulting in the widening of β-cell action potentials and a decreased firing frequency. Finally, these effects on channel function and excitability were augmented by the conjugating enzyme Ubc9 and rescued by the SUMO protease SENP1. Thus, protein SUMOylation can exert a strong inhibitory action on the voltage-dependent K⁺ channel Kv2.1 and can regulate cellular excitability in native β-cells.

Key words: Kv2.1, SUMO, Insulin, Ion channels, Islets of Langerhans, Voltage-dependent K⁺ channels

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