Burdakov Denis, Jensen Lise T, Alexopoulos Haris, Williams Rhiannan H, Fearon Ian M, O'Kelly Ita, Gerasimenko Oleg, Fugger Lars, Verkhratsky Alexei
Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, United Kingdom.
Neuron. 2006 Jun 1;50(5):711-22. doi: 10.1016/j.neuron.2006.04.032.
Glucose-inhibited neurons orchestrate behavior and metabolism according to body energy levels, but how glucose inhibits these cells is unknown. We studied glucose inhibition of orexin/hypocretin neurons, which promote wakefulness (their loss causes narcolepsy) and also regulate metabolism and reward. Here we demonstrate that their inhibition by glucose is mediated by ion channels not previously implicated in central or peripheral glucose sensing: tandem-pore K(+) (K(2P)) channels. Importantly, we show that this electrical mechanism is sufficiently sensitive to encode variations in glucose levels reflecting those occurring physiologically between normal meals. Moreover, we provide evidence that glucose acts at an extracellular site on orexin neurons, and this information is transmitted to the channels by an intracellular intermediary that is not ATP, Ca(2+), or glucose itself. These results reveal an unexpected energy-sensing pathway in neurons that regulate states of consciousness and energy balance.
葡萄糖抑制性神经元根据身体能量水平协调行为和新陈代谢，但葡萄糖如何抑制这些细胞尚不清楚。我们研究了食欲素/下丘脑泌素神经元的葡萄糖抑制作用，这些神经元促进清醒（它们的缺失会导致发作性睡病），还调节新陈代谢和奖赏。在此我们证明，它们受葡萄糖的抑制是由以前未涉及中枢或外周葡萄糖感应的离子通道介导的：串联孔钾离子（K(2P)）通道。重要的是，我们表明这种电机制足够敏感，能够编码反映正常餐间生理发生的葡萄糖水平变化。此外，我们提供证据表明葡萄糖作用于食欲素神经元的细胞外位点，并且该信息通过不是ATP、Ca(2+)或葡萄糖本身的细胞内中介传递给通道。这些结果揭示了神经元中一条意想不到的调节意识状态和能量平衡的能量感应途径。
