title: Selective down-regulation of KV2.1 function contributes to enhanced arterial tone during diabetes.
abstract: 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 Ca(2+)-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.
authors: From the Department of Pharmacology, University of California, Davis, California 95616.
authors: Madeline
authors: M
authors: Nieves-Cintrón
authors: From the Department of Pharmacology, University of California, Davis, California 95616.
authors: Matthew A
authors: MA
authors: Nystoriak
authors: From the Department of Pharmacology, University of California, Davis, California 95616.
authors: Maria Paz
authors: MP
authors: Prada
authors: From the Department of Pharmacology, University of California, Davis, California 95616.
authors: Kenneth
authors: K
authors: Johnson
authors: From the Department of Pharmacology, University of California, Davis, California 95616.
authors: William
authors: W
authors: Fayer
authors: the Department of Pharmacology, University of Colorado, Denver, Colorado 80045, and.
authors: Mark L
authors: ML
authors: Dell'Acqua
authors: the Howard Hughes Medical Institute and Department of Pharmacology, University of Washington, Seattle, Washington 98195.
authors: John D
authors: JD
authors: Scott
authors: From the Department of Pharmacology, University of California, Davis, California 95616, mfnavedo@ucdavis.edu.
authors: Manuel F
authors: MF
authors: Navedo
mesh_terms: D000818:Animals; D001158:Arteries / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000503:physiopathology; D015536:Down-Regulation; D051379:Mice; D008810:Mice, Inbred C57BL; D009129:Muscle Tonus / Q000502:physiology*; D051669:Shab Potassium Channels / Q000502:physiology*
chemical_list: C496990:Kcnb1 protein, mouse; D051669:Shab Potassium Channels
keywords: AKAP150; Cerebral Arteries; Gene Regulation; High Fat Diet Mouse; Hyperglycemia; Ion Channel; Scaffold Protein; Type 2 Diabetes; Vascular Smooth Muscle Cells