AKAP150 Contributes to Enhanced Vascular Tone by Facilitating BKCa Channel Remodeling in Hyperglycemia and Diabetes
Rationale: Increased contractility of arterial myocytes and enhanced vascular tone during hyperglycemia and diabetes may arise from impaired large conductance Ca2+-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.
Objective: To test the hypothesis that AKAP150-dependent CaN signaling mediates BKCa β1 downregulation and impaired vascular BKCa channel function during hyperglycemia and diabetes.
Methods and Results: 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 Ca2+ influx via voltage-gated L-type Ca2+ 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.
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.
- high fat mice
- transcription factors
- membrane transport/ion channels
- intracellular calcium
- hypertension, high blood pressure
- smooth muscle cell
- potassium channels
- Received July 9, 2013.
- Revision received December 5, 2013.
- Accepted December 9, 2013.