Carnitine palmitoyltransferase 1C (CPT1C) is a sensor of malonyl-CoA and is located in the ER of neurons. AMPA receptors (AMPARs) mediate fast excitatory neurotransmission in the brain and play a key role in synaptic plasticity. In the present study, we demonstrate across different metabolic stress conditions that modulate malonyl-CoA levels in cortical neurons that CPT1C regulates the trafficking of the major AMPAR subunit, GluA1, through the phosphatidyl-inositol-4-phosphate (PI(4)P) phosphatase SAC1. In normal conditions, CPT1C down-regulates SAC1 catalytic activity, allowing efficient GluA1 trafficking to the plasma membrane. However, under low malonyl-CoA levels, such as during glucose depletion, CPT1C-dependent inhibition of SAC1 is released, facilitating SAC1’s translocation to ER-TGN contact sites to decrease TGN PI(4)P pools and trigger GluA1 retention at the TGN. Results reveal that GluA1 trafficking is regulated by CPT1C sensing of malonyl-CoA and provide the first report of a SAC1 inhibitor. Moreover, they shed light on how nutrients can affect synaptic function and cognition.

中文翻译：

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CPT1C 感知营养物质控制 SAC1 活性以调节 AMPA 受体运输

肉碱棕榈酰转移酶 1C (CPT1C) 是丙二酰辅酶 A 的传感器，位于神经元的 ER 中。AMPA 受体 (AMPAR) 介导大脑中的快速兴奋性神经传递，并在突触可塑性中发挥关键作用。在本研究中，我们证明了在调节皮质神经元丙二酰辅酶A水平的不同代谢应激条件下，CPT1C通过磷脂酰肌醇4-磷酸（PI(4)P）调节主要AMPAR亚基GluA1的运输磷酸酶SAC1。在正常情况下，CPT1C 下调 SAC1 催化活性，从而使 GluA1 有效运输至质膜。然而，在低丙二酰辅酶A水平下，例如在葡萄糖耗尽期间，SAC1的CPT1C依赖性抑制被释放，促进SAC1易位至ER-TGN接触位点，从而减少TGN PI(4)P库并触发GluA1在TGN处的保留。结果表明，GluA1 运输受丙二酰辅酶 A 的 CPT1C 感应调节，并提供了 SAC1 抑制剂的第一份报告。此外，它们还揭示了营养物质如何影响突触功能和认知。