ATP敏感性钾通道(K-ATP)编码基因的功能缺失或获得突变,KCNJ8和ABCC9,引起人类中枢神经系统紊乱,发病机制不明。这里,用老鼠,斑马鱼,和细胞培养模型,我们研究了由K-ATP通道功能改变引起的脑功能障碍的细胞和分子原因。我们表明,含有KCNJ8/ABCC9的K-ATP通道功能的遗传/化学抑制或激活导致脑选择性抑制或促进动脉/小动脉血管平滑肌细胞(VSMC)分化,分别。我们进一步表明,大脑VSMC是从含有KCNJ8/ABCC9的K-ATP通道表达壁系细胞祖细胞发展而来的,并且K-ATP通道细胞通过电压依赖性钙通道调节细胞内Ca2振荡来自主调节VSMC分化。与有缺陷的VSMC开发一致,Kcnj8基因敲除小鼠表现出血管收缩能力和神经元诱发的血管舒张功能不足,导致局部充血。我们的结果证明了含有KCNJ8/ABCC9的K-ATP通道在脑VSMC分化中的作用。这反过来又是微调脑血流所必需的。
Loss- or gain-of-function mutations in ATP-sensitive potassium channel (K-ATP)-encoding genes,
KCNJ8 and ABCC9, cause human central nervous system disorders with unknown pathogenesis. Here, using mice, zebrafish, and cell culture models, we investigated cellular and molecular causes of brain dysfunctions derived from altered K-ATP channel function. We show that genetic/chemical inhibition or activation of
KCNJ8/ABCC9-containing K-ATP channel function leads to brain-selective suppression or promotion of arterial/arteriolar vascular smooth muscle cell (VSMC) differentiation, respectively. We further show that brain VSMCs develop from
KCNJ8/ABCC9-containing K-ATP channel-expressing mural cell progenitor and that K-ATP channel cell autonomously regulates VSMC differentiation through modulation of intracellular Ca2+ oscillation via voltage-dependent calcium channels. Consistent with defective VSMC development,
Kcnj8 knockout mice showed deficiency in vasoconstrictive capacity and neuronal-evoked vasodilation leading to local hyperemia. Our results demonstrate a role for
KCNJ8/ABCC9-containing K-ATP channels in the differentiation of brain VSMC, which in turn is necessary for fine-tuning of cerebral blood flow.