Genetic ablation or mutation of AKAP150 to prevent calcineurin anchoring protected against BKCa channel remodeling, NFATc3 activation, and augmented vasoconstriction in hyperglycemic mice.
Subcellular anchoring of CaN by AKAP150 is a key molecular determinant of vascular BKCa channel remodeling and contributes to vasoconstriction in diabetes mellitus.
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(+) (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. METHODS AND 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.
Nystoriak et al. (2013) studied Hyperglycemia and diabetes mellitus. Genetic ablation or mutation of AKAP150 vs. Wild-type animals on high-fat diet was evaluated on BKCa channel remodeling, CaN/NFATc3 activation, and resistance artery constriction. Genetic ablation or mutation of AKAP150 to prevent calcineurin anchoring protected against BKCa channel remodeling, NFATc3 activation, and augmented vasoconstriction in hyperglycemic mice.