Selective down-regulation of KV2.1 function contributes to enhanced arterial tone during diabetes

Madeline Nieves-Cintro, Matthew A. Nystoriak, Maria Paz Prada, Kenneth Johnson, William Fayer, Mark L. Dell'Acqua, John D. Scott, Manuel F. Navedo

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


Enhanced arterial tone is a leading cause of vascular complications during diabetes. Voltage-gated K+ (KV) channels are key regulators of vascular smooth muscle cells (VSMCs) contractility and arterial tone. Whether impaired KV channel function contributes to enhance arterial tone during diabetes is unclear. Here, we demonstrate a reduction in KV-mediated currents (IKv) in VSMCs from a high fat diet (HFD) mouse model of type 2 diabetes. In particular, IKv sensitive to stromatoxin (ScTx), a potent KV2 blocker, were selectively reduced in diabetic VSMCs. This was associated with decreased KV2-mediated regulation of arterial tone and suppression of the KV2.1 subunit mRNA and protein in VSMCs/arteries isolated from HFD mice. We identified protein kinase A anchoring protein 150 (AKAP150), via targeting of the phosphatase calcineurin (CaN), and the transcription factor nuclear factor of activated T-cells c3 (NFATc3) as required determinants of KV2.1 suppression during diabetes. Interestingly, substantial reduction in transcript levels for KV2.1 preceded down-regulation of large conductance Ca2+-activated K+ (BKCa) channel β1 subunits, which are ultimately suppressed in chronic hyperglycemia to a similar extent. Together, our study supports the concept that transcriptional suppression of KV2.1 by activation of the AKAP150-CaN/NFATc3 signaling axis contributes to enhanced arterial tone during diabetes.

Original languageEnglish (US)
Pages (from-to)7918-7929
Number of pages12
JournalJournal of Biological Chemistry
Issue number12
StatePublished - Mar 20 2015

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology


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