Ashrafi Ghazaleh, Wu Zhuhao, Farrell Ryan J, Ryan Timothy A
Department of Biochemistry, Weill Cornell Medicine, New York, NY 10021, USA.
Laboratory of Brain Development and Repair, The Rockefeller University, New York, NY 10065, USA.
Neuron. 2017 Feb 8;93(3):606-615.e3. doi: 10.1016/j.neuron.2016.12.020. Epub 2017 Jan 19.
The brain is highly sensitive to proper fuel availability as evidenced by the rapid decline in neuronal function during ischemic attacks and acute severe hypoglycemia. We previously showed that sustained presynaptic function requires activity-driven glycolysis. Here, we provide strong evidence that during action potential (AP) firing, nerve terminals rely on the glucose transporter GLUT4 as a glycolytic regulatory system to meet the activity-driven increase in energy demands. Activity at synapses triggers insertion of GLUT4 into the axonal plasma membrane driven by activation of the metabolic sensor AMP kinase. Furthermore, we show that genetic ablation of GLUT4 leads to an arrest of synaptic vesicle recycling during sustained AP firing, similar to what is observed during acute glucose deprivation. The reliance on this biochemical regulatory system for "exercising" synapses is reminiscent of that occurring in exercising muscle to sustain cellular function and identifies nerve terminals as critical sites of proper metabolic control.
大脑对适当的能量供应高度敏感，缺血性发作和急性严重低血糖期间神经元功能的迅速下降就证明了这一点。我们之前表明，持续的突触前功能需要活动驱动的糖酵解。在这里，我们提供了强有力的证据，即在动作电位（AP）发放期间，神经末梢依靠葡萄糖转运蛋白GLUT4作为糖酵解调节系统，以满足活动驱动的能量需求增加。突触处的活动触发GLUT4插入轴突质膜，这是由代谢传感器AMP激酶的激活驱动的。此外，我们表明，GLUT4的基因敲除会导致在持续的AP发放期间突触小泡循环停滞，这与急性葡萄糖剥夺期间观察到的情况类似。对这种用于“锻炼”突触的生化调节系统的依赖让人联想到锻炼肌肉时发生的情况，以维持细胞功能，并将神经末梢确定为适当代谢控制的关键部位。
