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

被引:72
|
作者
Dai, Xiao-Qing [1 ,2 ]
Kolic, Jelena [1 ,2 ]
Marchi, Paolo [1 ]
Sipione, Simonetta [1 ]
MacDonald, Patrick E. [1 ,2 ]
机构
[1] Univ Alberta, Dept Pharmacol, Edmonton, AB T6G 2E1, Canada
[2] Univ Alberta, Alberta Diabet Inst, Edmonton, AB T6G 2E1, Canada
基金
加拿大创新基金会;
关键词
Kv2.1; SUMO; Insulin; Ion channels; Islets of Langerhans; Voltage-dependent K+ channels; DEPENDENT INSULIN-SECRETION; K+ CHANNELS; POTASSIUM CURRENT; SUMO; EXPRESSION; ISLETS;
D O I
10.1242/jcs.036632
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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 beta-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 beta-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 beta-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 beta-cells.
引用
收藏
页码:775 / 779
页数:5
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