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Control of Kv2.2 expression by pyruvate-isocitrate cycling regulates glucose-stimulated insulin secretion.
Mette V Jensen, Jonathan M Haldeman, Hengtao Zhang, Danhong Lu, Mark O Huising, Wylie W Vale, Hans E Hohmeier, Paul Rosenberg, Christopher B Newgard
J. Biol. Chem.,
Recent studies have shown that the pyruvate-isocitrate cycling pathway, involving the mitochondrial citrate/isocitrate carrier (CIC) and the cytosolic NADP-dependent isoform of 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, CIC, or Kv2.2 expression impairs GSIS, and the effect of ICDc knockdown is rescued by re-expression of Kv2.2. Moreover, chronic exposure of β-cells to elevated fatty acids, which impairs GSIS, results in decreased expression of Kv2.2. Surprisingly, knockdown of ICDc or Kv2.2 increases rather than decreases outward K+ current in the 832/13 β-cell line. Immunoprecipitation studies demonstrate interaction of Kv2.1 and Kv2.2, and co-overexpression of the two channels reduces outward K+ current compared to overexpression of Kv2.1 alone. Also, siRNA-mediated knockdown of ICDc enhances the suppressive effect of the Kv2.1-selective inhibitor stromatoxin1 (ScTx1) 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.