Increased contractility of arterial myocytes and enhanced vascular tone during hyperglycemia and diabetes mellitus may arise from impaired large-conductance Ca²⁺-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.

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.

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 Ca²⁺ influx via voltage-gated L-type Ca²⁺ 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.

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.