From the Department of Pharmacology, University of California, Davis (M.A.N., M.N.-C., C.B.N., C.-Y.C., J.L.P., L.T.I., D.M.B., M.F.N.); Department of Pharmacology, University of Colorado, Denver (M.L.D.); Department of Pharmacology, Howard Hughes Medical Institute, University of Washington, Seattle, WA (P.J.N., S.A.H., J.D.S.); and Department of Physiology and Biophysics, University of Washington, Seattle (L.F.S.).
Circ Res. 2014 Feb 14;114(4):607-15. doi: 10.1161/CIRCRESAHA.114.302168. Epub 2013 Dec 9.
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.
To test the hypothesis that AKAP150-dependent CaN signaling mediates BKCa β1 downregulation and impaired vascular BKCa channel function during hyperglycemia and diabetes mellitus.
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.
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.
在高血糖和糖尿病期间，动脉平滑肌细胞的收缩性增加和血管张力增强可能源于大电导钙激活钾（BKCa）通道功能受损。支架蛋白蛋白激酶 A 锚定蛋白 150（AKAP150）是钙调神经磷酸酶（CaN）的关键调节剂，已知钙调神经磷酸酶调节调节 BKCaβ1 亚基的表达。AKAP150 是否在高血糖和糖尿病期间调节 BKCa 通道的抑制尚不清楚。
测试假设，即 AKAP150 依赖性 CaN 信号转导介导高血糖和糖尿病期间 BKCaβ1 下调和血管 BKCa 通道功能障碍。
我们发现，AKAP150 是 BKCa 通道重塑、CaN/激活 T 细胞核因子 c3（NFATc3）激活和高血糖动物高脂饮食抵抗动脉的重要决定因素。AKAP150 的基因缺失可防止这些改变，包括增强的血管收缩。d-葡萄糖依赖性抑制 BKCa 通道β1 亚基需要通过电压门控 L 型钙（Ca2+）通道的 Ca2+内流和 CaN/NFATc3 信号通路的动员。值得注意的是，表达无法锚定 CaN 的突变 AKAP150 的高脂肪饮食小鼠抵抗 NFATc3 的激活和 BKCaβ1 亚基的下调，并减轻高脂肪饮食引起的动脉血压升高。
我们的结果支持一种模型，即 AKAP150 通过 CaN 的亚细胞锚定是血管 BKCa 通道重塑的关键分子决定因素，这有助于糖尿病期间的血管收缩。
