Mechanisms of CPT1C-Dependent AMPAR trafficking enhancement
Author
Gratacòs-Batlle, Esther
Olivella, Mireia
Sánchez-Fernández, Nuria
Yefimenko, Natalia
MIguez-Cabello, Federico
Fadó Andrés, Rut
Casals i Farré, Núria
Gasull, Xavier
Ambrosio, Santiago
Soto, David
Publication date
2018-08-08ISSN
1662-5099
Abstract
In neurons, AMPA receptor (AMPAR) function depends essentially on their constituent
components: the ion channel forming subunits and ion channel associated proteins.
On the other hand, AMPAR trafficking is tightly regulated by a vast number of intracellular
neuronal proteins that bind to AMPAR subunits. It has been recently shown that the
interaction between the GluA1 subunit of AMPARs and carnitine palmitoyltransferase
1C (CPT1C), a novel protein partner of AMPARs, is important in modulating surface
expression of these ionotropic glutamate receptors. Indeed, synaptic transmission in
CPT1C knockout (KO) mice is diminished supporting a positive trafficking role for that
protein. However, the molecular mechanisms of such modulation remain unknown
although a putative role of CPT1C in depalmitoylating GluA1 has been hypothesized.
Here, we explore that possibility and show that CPT1C effect on AMPARs is likely due
to changes in the palmitoylation state of GluA1. Based on in silico analysis, Ser 252,
His 470 and Asp 474 are predicted to be the catalytic triad responsible for CPT1C
palmitoyl thioesterase (PTE) activity. When these residues are mutated or when PTE
activity is inhibited, the CPT1C effect on AMPAR trafficking is abolished, validating
the CPT1C catalytic triad as being responsible for PTE activity on AMPAR. Moreover,
the histidine residue (His 470) of CPT1C is crucial for the increase in GluA1 surface
expression in neurons and the H470A mutation impairs the depalmitoylating catalytic
activity of CPT1C. Finally, we show that CPT1C effect seems to be specific for this
CPT1 isoform and it takes place solely at endoplasmic reticulum (ER). This work adds
another facet to the impressive degree of molecular mechanisms regulating AMPAR
physiology.
Document Type
Article
Document version
Accepted version
Language
English
Subject (CDU)
61 - Medical sciences
616.8 - Neurology. Neuropathology. Nervous system
Keywords
Neurones
Neurons
Neuronas
Hipocamp
Hippocampus (Brain)
Neurociències
Neurosciences
Neurociencias
CPT1C
AMPARs
Pages
18
Publisher
Frontiers Media
Collection
11;275
Is part of
Frontiers in Molecular Neuroscience
Citation
Gratacòs-Batlle, Esther; Olivella, Mireia; Sánchez-Fernández, Nuria; Yefimenko, Natalia; Miguez-Cabello, Federico; Fadó Andrés, Rut; Casals, Núria; Gasull, Xavier; Ambrosio, Santiago; Soto, David. «Mechanisms of CPT1C-Dependent AMPAR trafficking enhancement». Frontiers in Molecular Neuroscience, 2018, vol. 11, art. 275. Disponible en: <https://www.frontiersin.org/articles/10.3389/fnmol.2018.00275/full>. Fecha de acceso: 16 oct. 2019. DOI: 10.3389/fnmol.2018.00275
This item appears in the following Collection(s)
- Ciències de la Salut [725]
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