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Circulation research [journal]
- AKAP150 Contributes to Enhanced Vascular Tone by Facilitating BKCa Channel Remodeling in Hyperglycemia and Diabetes. [JOURNAL ARTICLE]
- Circ Res 2013 Dec 9.
Increased contractility of arterial myocytes and enhanced vascular tone during hyperglycemia and diabetes may arise from impaired large conductance Ca(2+)-activated K(+) (BKCa) channel function. The scaffolding protein AKAP150 is a key regulator of calcineurin (CaN), a phosphatase known to modulate expression of the regulatory BKCa β1 subunit. Whether AKAP150 mediates BKCa channel suppression during hyperglycemia and diabetes is unknown.To test the hypothesis that AKAP150-dependent CaN signaling mediates BKCa β1 downregulation and impaired vascular BKCa channel function during hyperglycemia and diabetes.We found that AKAP150 is an important determinant of BKCa channel remodeling, CaN/NFATc3 activation, and resistance artery constriction in hyperglycemic animals on high fat diet (HFD). 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, HFD mice expressing a mutant AKAP150 unable to anchor CaN resisted activation of NFATc3 and downregulation of BKCa β1 subunits, and attenuated HFD-induced elevation in arterial blood pressure.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.
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