Sensing of nutrients by CPT1C controls SAC1 activity to regulate AMPA receptor trafficking

Maria Casas, Rut Fadó, José Luis Domínguez, Aina Roig, Moena Kaku, Shigeru Chohnan, Montse Solé, Mercedes Unzeta, Alfredo Jesús Miñano-Molina, José Rodríguez-Álvarez, Eamonn James Dickson, Núria Casals

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish (US)
JournalThe Journal of cell biology
Volume219
Issue number10
DOIs
StatePublished - Oct 5 2020

ASJC Scopus subject areas

  • Cell Biology

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