VIB Center for Biology of Disease, Katholieke Universiteit Leuven, Leuven, Belgium.
EMBO J. 2012 Apr 4;31(7):1764-73. doi: 10.1038/emboj.2012.31. Epub 2012 Feb 17.
The deregulation of brain cholesterol metabolism is typical in acute neuronal injury (such as stroke, brain trauma and epileptic seizures) and chronic neurodegenerative diseases (Alzheimer's disease). Since both conditions are characterized by excessive stimulation of glutamate receptors, we have here investigated to which extent excitatory neurotransmission plays a role in brain cholesterol homeostasis. We show that a short (30 min) stimulation of glutamatergic neurotransmission induces a small but significant loss of membrane cholesterol, which is paralleled by release to the extracellular milieu of the metabolite 24S-hydroxycholesterol. Consistent with a cause-effect relationship, knockdown of the enzyme cholesterol 24-hydroxylase (CYP46A1) prevented glutamate-mediated cholesterol loss. Functionally, the loss of cholesterol modulates the magnitude of the depolarization-evoked calcium response. Mechanistically, glutamate-induced cholesterol loss requires high levels of intracellular Ca(2+), a functional stromal interaction molecule 2 (STIM2) and mobilization of CYP46A1 towards the plasma membrane. This study underscores the key role of excitatory neurotransmission in the control of membrane lipid composition, and consequently in neuronal membrane organization and function.
脑胆固醇代谢的失调在急性神经元损伤（如中风、脑创伤和癫痫发作）和慢性神经退行性疾病（阿尔茨海默病）中很典型。由于这两种情况的特征都是谷氨酸受体的过度刺激，我们在这里研究了兴奋性神经递质传递在脑胆固醇稳态中起了何种作用。我们表明，谷氨酸能神经传递的短暂（30 分钟）刺激会导致膜胆固醇的少量但显著损失，这与代谢产物 24S-羟基胆固醇向细胞外环境的释放相平行。与因果关系一致的是，胆固醇 24-羟化酶（CYP46A1）的敲低阻止了谷氨酸介导的胆固醇损失。从功能上看，胆固醇的损失调节了去极化诱发的钙反应的幅度。从机制上讲，谷氨酸诱导的胆固醇损失需要高水平的细胞内 Ca(2+)、功能性基质相互作用分子 2（STIM2）以及 CYP46A1 向质膜的迁移。这项研究强调了兴奋性神经递质传递在控制膜脂质组成方面的关键作用，进而在神经元膜的组织和功能方面发挥关键作用。
