title: AKAP150 contributes to enhanced vascular tone by facilitating large-conductance Ca2+-activated K+ channel remodeling in hyperglycemia and diabetes mellitus.
abstract: BACKGROUND
  Increased contractility of arterial myocytes and enhanced vascular tone during hyperglycemia and diabetes mellitus may arise from impaired large-conductance Ca(2+)-activated K(+) (BKCa) channel function. The scaffolding protein A-kinase anchoring protein 150 (AKAP150) is a key regulator of calcineurin (CaN), a phosphatase known to modulate the expression of the regulatory BKCa β1 subunit. Whether AKAP150 mediates BKCa channel suppression during hyperglycemia and diabetes mellitus is unknown.
  
  
  OBJECTIVE
  To test the hypothesis that AKAP150-dependent CaN signaling mediates BKCa β1 downregulation and impaired vascular BKCa channel function during hyperglycemia and diabetes mellitus.
  
  
  RESULTS
  We found that AKAP150 is an important determinant of BKCa channel remodeling, CaN/nuclear factor of activated T-cells c3 (NFATc3) activation, and resistance artery constriction in hyperglycemic animals on high-fat diet. Genetic ablation of AKAP150 protected against these alterations, including augmented vasoconstriction. d-glucose-dependent suppression of BKCa channel β1 subunits required Ca(2+) influx via voltage-gated L-type Ca(2+) channels and mobilization of a CaN/NFATc3 signaling pathway. Remarkably, high-fat diet mice expressing a mutant AKAP150 unable to anchor CaN resisted activation of NFATc3 and downregulation of BKCa β1 subunits and attenuated high-fat diet-induced elevation in arterial blood pressure.
  
  
  CONCLUSIONS
  Our results support a model whereby subcellular anchoring of CaN by AKAP150 is a key molecular determinant of vascular BKCa channel remodeling, which contributes to vasoconstriction during diabetes mellitus.
authors: From the Department of Pharmacology, University of California, Davis (M.A.N., M.N.-C., C.B.N., C.-Y.C., J.L.P., L.T.I., D.M.B., M.F.N.); Department of Pharmacology, University of Colorado, Denver (M.L.D.); Department of Pharmacology, Howard Hughes Medical Institute, University of Washington, Seattle, WA (P.J.N., S.A.H., J.D.S.); and Department of Physiology and Biophysics, University of Washington, Seattle (L.F.S.).
authors: Matthew A
authors: MA
authors: Nystoriak
authors: Madeline
authors: M
authors: Nieves-Cintrón
authors: Patrick J
authors: PJ
authors: Nygren
authors: Simon A
authors: SA
authors: Hinke
authors: C Blake
authors: CB
authors: Nichols
authors: Chao-Yin
authors: CY
authors: Chen
authors: Jose L
authors: JL
authors: Puglisi
authors: Leighton T
authors: LT
authors: Izu
authors: Donald M
authors: DM
authors: Bers
authors: Mark L
authors: ML
authors: Dell'acqua
authors: John D
authors: JD
authors: Scott
authors: Luis F
authors: LF
authors: Santana
authors: Manuel F
authors: MF
authors: Navedo
mesh_terms: D054758:A Kinase Anchor Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D004041:Dietary Fats / Q000494:pharmacology; D055879:Gene Knock-In Techniques; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D006973:Hypertension / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits / Q000235:genetics / Q000378:metabolism*; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000502:physiology; D050778:NFATC Transcription Factors / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D014118:Toxins, Biological / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*
chemical_list: D054758:A Kinase Anchor Proteins; C520665:Akap5 protein, mouse; D004041:Dietary Fats; C543091:Kcnmb1 protein, mouse; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits; D051036:Large-Conductance Calcium-Activated Potassium Channels; D050778:NFATC Transcription Factors; C494009:Nfatc3 protein, mouse; D010455:Peptides; D014118:Toxins, Biological; C064719:iberiotoxin
keywords: calcineurin; hyperglycemia; hypertension; ion channels; potassium channels