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

GuA1-containing AMPA receptors play a key role in synaptic plasticity and cognition. Casas et al. demonstrate that the sensing of nutrients by CPT1C regulates the phosphatase activity of SAC1, and consequently PI(4)P levels, at the contact sites between the endoplasmic reticulum and the trans-Golgi...

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Detalles Bibliográficos
Autores: Casas, Maria|||0000-0002-5246-8874, Fadó, Rut|||0000-0002-3293-2342, Domínguez, José Luis, Roig, Aina, Kaku, Moena, Chohnan, Shigeru|||0000-0002-4624-927X, Solé Piñol, Montserrat|||0000-0003-4240-6562, Unzeta López, Mercedes|||0000-0002-7113-3383, Miñano Molina, Alfredo Jesús|||0000-0002-7761-5682, Rodríguez Álvarez, José|||0000-0001-8582-8082, Dickson, Eamonn James|||0000-0001-8619-7630, Casals, Nuria|||0000-0002-6719-4300
Tipo de recurso: artículo
Fecha de publicación:2020
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:252904
Acceso en línea:https://ddd.uab.cat/record/252904
https://dx.doi.org/urn:doi:10.1083/jcb.201912045
Access Level:acceso abierto
Descripción
Sumario:GuA1-containing AMPA receptors play a key role in synaptic plasticity and cognition. Casas et al. demonstrate that the sensing of nutrients by CPT1C regulates the phosphatase activity of SAC1, and consequently PI(4)P levels, at the contact sites between the endoplasmic reticulum and the trans-Golgi network to control the trafficking of GluA1 receptors to the cell surface of neurons. 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.

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