Department of Biochemistry, New York University School of Medicine, New York, New York 10016, USA.
J Neurosci. 2011 Feb 9;31(6):1991-9. doi: 10.1523/JNEUROSCI.1850-09.2011.
Glucose transporter 3 (GLUT3) is the main facilitative glucose transporter in neurons. Glucose provides neurons with a critical energy source for neuronal activity. However, the mechanism by which neuronal activity controls glucose influx via GLUT3 is unknown. We investigated the influence of synaptic stimulation on GLUT3 surface expression and glucose import in primary cultured cortical and hippocampal neurons. Synaptic activity increased surface expression of GLUT3 leading to an elevation of intracellular glucose. The effect was blocked by NMDA receptor (NMDAR) and neuronal nitric oxide synthase (nNOS) inhibition. The Akt inhibitor I (Akt-I) blocked NMDAR-induced GLUT3 surface expression while a nNOS-phosphomimetic mutant (S1412D) enhanced GLUT3 expression at cell surface. These results suggest that NMDAR/Akt-dependent nNOS phosphorylation is coupled to GLUT3 trafficking. We demonstrated that activation of cGMP-dependent protein kinase (cGK) increased the surface expression of GLUT3, which was repressed by Rp-8-pCPT-cGMPS, a potent cell-permeable inhibitor of cGKs. These studies characterize the molecular basis for activity-dependent increases in surface GLUT3 after stimulation of the NMDARs. NMDAR-induced increase in surface GLUT3 represents a novel pathway for control of energy supply during neuronal activity that is critical for maintaining glucose homeostasis during neuronal transmission.
葡萄糖转运蛋白 3（GLUT3）是神经元中主要的易化葡萄糖转运蛋白。葡萄糖为神经元的活动提供了关键的能量来源。然而，神经元活动通过 GLUT3 控制葡萄糖内流的机制尚不清楚。我们研究了突触刺激对原代培养皮质和海马神经元中 GLUT3 表面表达和葡萄糖摄取的影响。突触活动增加了 GLUT3 的表面表达，导致细胞内葡萄糖水平升高。该效应被 NMDA 受体（NMDAR）和神经元型一氧化氮合酶（nNOS）抑制所阻断。Akt 抑制剂 I（Akt-I）阻断了 NMDAR 诱导的 GLUT3 表面表达，而 nNOS 磷酸化模拟突变体（S1412D）增强了 GLUT3 在细胞表面的表达。这些结果表明，NMDAR/Akt 依赖性 nNOS 磷酸化与 GLUT3 转运有关。我们证明，cGMP 依赖性蛋白激酶（cGK）的激活增加了 GLUT3 的表面表达，而 cGK 的有效细胞通透性抑制剂 Rp-8-pCPT-cGMPS 则抑制了 GLUT3 的表面表达。这些研究描述了 NMDAR 刺激后表面 GLUT3 活性依赖性增加的分子基础。NMDAR 诱导的 GLUT3 表面增加代表了一种新的途径，用于控制神经元活动期间的能量供应，这对于维持神经元传递期间的葡萄糖稳态至关重要。
