Abstract
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.
Highlights
Pyruvate-isocitrate cycling is involved in control of glucose-stimulated insulin secretion (GSIS), but the underlying mechanisms are unknown
We demonstrate that pyruvateisocitrate cycling regulates expression of the voltage-gated potassium channel family member Kv2.2 in islet -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
Kv2.2 mRNA Levels Are Lowered in 832/13 Cells with Suppressed Pyruvate-Isocitrate Cycling Activity—Clear correlations between pyruvate cycling and NADPH production [7, 11, 23] and between NADPH production and insulin secretion [8, 11, 43] have been established in recent years
Summary
Pyruvate-isocitrate cycling is involved in control of glucose-stimulated insulin secretion (GSIS), but the underlying mechanisms are unknown. Results: Pyruvate-isocitrate cycling controls expression of the voltage-gated potassium channel family member Kv2.2 in islet cells. 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). Isocitrate is converted to ␣-ketoglutarate in a reaction catalyzed by cytosolic NADP-dependent isocitrate dehydrogenase (ICDc) Consistent with this model, silencing of either CIC or ICDc causes marked impairment of GSIS in -cell lines and primary rat islets [11, 23]. Chronic exposure of 832/13 cells to elevated levels of fatty acids, a maneuver that causes impairment of GSIS and loss of glucose regulation of pyruvate cycling activity [6], resulted in suppression of Kv2.2 but not Kv2.1 expression. Our findings point to Kv2.2 as a potential new target for reversing the -cell dysfunction observed in type 2 diabetes
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
