Availability of neurotransmitter glutamate is diminished when β‐hydroxybutyrate replaces glucose in cultured neurons
Availability of neurotransmitter glutamate is diminished when β‐hydroxybutyrate replaces glucose in cultured neurons
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当β-羟基丁酸取代培养神经元中的葡萄糖时，神经递质谷氨酸的可用性会降低
DOI：
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发表时间：
2009
影响因子：
4.7
通讯作者：
H. Waagepetersen
中科院分区：
文献类型：
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作者：
T. M. Lund;Ø. Risa;U. Sonnewald;A. Schousboe;H. Waagepetersen
在低葡萄糖可用性的情况下，如在饥饿期间或在接受生酮饮食治疗的患者中，酮体作为大脑的替代能量底物。酮体通过局限于线粒体的独特途径代谢。我们比较了培养的谷氨酸能神经元中[2,4‐13C]β -羟基丁酸盐和[1,6‐13C]葡萄糖的代谢，并研究了神经元活动对天冬氨酸-谷氨酸稳态的影响，这是大脑兴奋性活动的重要组成部分。与[1,6 - 13C]葡萄糖相反，在[2,4 - 13C]β -羟基丁酸盐存在下，谷氨酸的13C掺入量和细胞含量较低，而天冬氨酸的13C含量较高。我们的研究结果表明，天冬氨酸-谷氨酸稳态的变化是由于细胞内苹果酸脱氢酶NADH的可用性降低，从而减少了使用β -羟基丁酸的神经元中苹果酸-天冬氨酸穿梭活性。在葡萄糖存在的情况下，谷氨酸含量在神经递质释放激活后显著下降，而在仅β -羟基丁酸存在的情况下，谷氨酸含量没有下降。因此，当代谢β -羟基丁酸时，可用于传递素释放的谷氨酸池的比例减少了，这与通过苹果酸-天冬氨酸穿梭体的强制性参与形成传递素谷氨酸的假设一致。
Ketone bodies serve as alternative energy substrates for the brain in cases of low glucose availability such as during starvation or in patients treated with a ketogenic diet. The ketone bodies are metabolized via a distinct pathway confined to the mitochondria. We have compared metabolism of [2,4‐13C]β‐hydroxybutyrate to that of [1,6‐13C]glucose in cultured glutamatergic neurons and investigated the effect of neuronal activity focusing on the aspartate–glutamate homeostasis, an essential component of the excitatory activity in the brain. The amount of 13C incorporation and cellular content was lower for glutamate and higher for aspartate in the presence of [2,4‐13C]β‐hydroxybutyrate as opposed to [1,6‐13C]glucose. Our results suggest that the change in aspartate–glutamate homeostasis is due to a decreased availability of NADH for cytosolic malate dehydrogenase and thus reduced malate–aspartate shuttle activity in neurons using β‐hydroxybutyrate. In the presence of glucose, the glutamate content decreased significantly upon activation of neurotransmitter release, whereas in the presence of only β‐hydroxybutyrate, no decrease in the glutamate content was observed. Thus, the fraction of the glutamate pool available for transmitter release was diminished when metabolizing β‐hydroxybutyrate, which is in line with the hypothesis of formation of transmitter glutamate via an obligatory involvement of the malate–aspartate shuttle.