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.
Sensing of nutrients by CPT1C controls SAC1 activity to regulate AMPA receptor trafficking
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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; Sensing of nutrients by CPT1C controls SAC1 activity to regulate AMPA receptor trafficking. J Cell Biol 5 October 2020; 219 (10): e201912045. doi: https://doi.org/10.1083/jcb.201912045
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