Rationale
:
Increased contractility of arterial myocytes and enhanced vascular tone during hyperglycemia and diabetes mellitus may arise from impaired large-conductance Ca
2+
-activated K
+
(BK
Ca
) 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 BK
Ca
β1 subunit. Whether AKAP150 mediates BK
Ca
channel suppression during hyperglycemia and diabetes mellitus is unknown.
Objective
:
To test the hypothesis that AKAP150-dependent CaN signaling mediates BK
Ca
β1 downregulation and impaired vascular BK
Ca
channel function during hyperglycemia and diabetes mellitus.
Methods and Results
:
We found that AKAP150 is an important determinant of BK
Ca
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 BK
Ca
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 BK
Ca
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 BK
Ca
channel remodeling, which contributes to vasoconstriction during diabetes mellitus.
AKAP150 Contributes to Enhanced Vascular Tone by Facilitating Large-Conductance Ca
2+
-Activated K
+
Channel Remodeling in Hyperglycemia and Diabetes Mellitus
