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Control of voltage-gated potassium channel Kv2.2 expression by pyruvate-isocitrate cycling regulates glucose-stimulated insulin secretion.

Publication ,  Journal Article
Jensen, MV; Haldeman, JM; Zhang, H; Lu, D; Huising, MO; Vale, WW; Hohmeier, HE; Rosenberg, P; Newgard, CB
Published in: J Biol Chem
August 9, 2013

Recent studies have shown that the pyruvate-isocitrate cycling pathway, involving the mitochondrial citrate/isocitrate carrier and the cytosolic NADP-dependent isocitrate dehydrogenase (ICDc), is involved in control of glucose-stimulated insulin secretion (GSIS). Here we demonstrate that pyruvate-isocitrate cycling regulates expression of the voltage-gated potassium channel family member Kv2.2 in islet β-cells. siRNA-mediated suppression of ICDc, citrate/isocitrate carrier, or Kv2.2 expression impaired GSIS, and the effect of ICDc knockdown was rescued by re-expression of Kv2.2. Moreover, chronic exposure of β-cells to elevated fatty acids, which impairs GSIS, resulted in decreased expression of Kv2.2. Surprisingly, knockdown of ICDc or Kv2.2 increased rather than decreased outward K(+) current in the 832/13 β-cell line. Immunoprecipitation studies demonstrated interaction of Kv2.1 and Kv2.2, and co-overexpression of the two channels reduced outward K(+) current compared with overexpression of Kv2.1 alone. Also, siRNA-mediated knockdown of ICDc enhanced the suppressive effect of the Kv2.1-selective inhibitor stromatoxin1 on K(+) currents. Our data support a model in which a key function of the pyruvate-isocitrate cycle is to maintain levels of Kv2.2 expression sufficient to allow it to serve as a negative regulator of Kv channel activity.

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Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

August 9, 2013

Volume

288

Issue

32

Start / End Page

23128 / 23140

Location

United States

Related Subject Headings

  • Spider Venoms
  • Shab Potassium Channels
  • Rats, Sprague-Dawley
  • Rats
  • Pyruvic Acid
  • Potassium
  • Peptides
  • Models, Biological
  • Male
  • Isocitrates
 

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Jensen, M. V., Haldeman, J. M., Zhang, H., Lu, D., Huising, M. O., Vale, W. W., … Newgard, C. B. (2013). Control of voltage-gated potassium channel Kv2.2 expression by pyruvate-isocitrate cycling regulates glucose-stimulated insulin secretion. J Biol Chem, 288(32), 23128–23140. https://doi.org/10.1074/jbc.M113.491654
Jensen, Mette V., Jonathan M. Haldeman, Hengtao Zhang, Danhong Lu, Mark O. Huising, Wylie W. Vale, Hans E. Hohmeier, Paul Rosenberg, and Christopher B. Newgard. “Control of voltage-gated potassium channel Kv2.2 expression by pyruvate-isocitrate cycling regulates glucose-stimulated insulin secretion.J Biol Chem 288, no. 32 (August 9, 2013): 23128–40. https://doi.org/10.1074/jbc.M113.491654.
Jensen MV, Haldeman JM, Zhang H, Lu D, Huising MO, Vale WW, et al. Control of voltage-gated potassium channel Kv2.2 expression by pyruvate-isocitrate cycling regulates glucose-stimulated insulin secretion. J Biol Chem. 2013 Aug 9;288(32):23128–40.
Jensen, Mette V., et al. “Control of voltage-gated potassium channel Kv2.2 expression by pyruvate-isocitrate cycling regulates glucose-stimulated insulin secretion.J Biol Chem, vol. 288, no. 32, Aug. 2013, pp. 23128–40. Pubmed, doi:10.1074/jbc.M113.491654.
Jensen MV, Haldeman JM, Zhang H, Lu D, Huising MO, Vale WW, Hohmeier HE, Rosenberg P, Newgard CB. Control of voltage-gated potassium channel Kv2.2 expression by pyruvate-isocitrate cycling regulates glucose-stimulated insulin secretion. J Biol Chem. 2013 Aug 9;288(32):23128–23140.

Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

August 9, 2013

Volume

288

Issue

32

Start / End Page

23128 / 23140

Location

United States

Related Subject Headings

  • Spider Venoms
  • Shab Potassium Channels
  • Rats, Sprague-Dawley
  • Rats
  • Pyruvic Acid
  • Potassium
  • Peptides
  • Models, Biological
  • Male
  • Isocitrates