1. Sensing of nutrients by CPT1C controls SAC1 activity to regulate AMPA receptor trafficking
- Author
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Casas, Maria, Fadó, Rut, Domínguez, José Luis, Roig, Aina, Kaku, Moena, Chohnan, Shigeru, Solé, Montse, Unzeta, Mercedes, Miñano-Molina, Alfredo Jesús, Rodríguez-Álvarez, José, Dickson, Eamonn James, and Casals, Núria
- Subjects
Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Biological Sciences ,Neurosciences ,Underpinning research ,1.1 Normal biological development and functioning ,Neurological ,Animals ,Brain ,Carnitine O-Palmitoyltransferase ,Glucose ,Humans ,Malonyl Coenzyme A ,Membrane Proteins ,Mice ,Neurons ,Nutrients ,Phosphatidylinositol Phosphates ,Protein Transport ,Receptors ,AMPA ,Synaptic Transmission ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences - 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.
- Published
- 2020