Mechanisms of CPT1C-Dependent AMPAR Trafficking Enhancement.
Mechanisms of CPT1C-Dependent AMPAR Trafficking Enhancement.
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DOI：
10.3389/fnmol.2018.00275
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发表时间：
2018
影响因子：
4.8
通讯作者：
Soto D
中科院分区：
文献类型：
--
作者：
Gratacòs-Batlle E;Olivella M;Sánchez-Fernández N;Yefimenko N;Miguez-Cabello F;Fadó R;Casals N;Gasull X;Ambrosio S;Soto D
在神经元中，AMPA受体（AMPAR）的功能主要取决于其组成成分：离子通道形成亚基和离子通道相关蛋白。另一方面，AMPAR转运受到大量与AMPAR亚基结合的细胞内神经元蛋白的严格调控。最近的研究表明，AMPARs的GluA1亚基与肉碱棕榈酰基转移酶1C （CPT1C）之间的相互作用在调节这些嗜离子性谷氨酸受体的表面表达中是重要的。事实上，CPT1C敲除（KO）小鼠的突触传递减少，支持该蛋白的积极运输作用。然而，这种调节的分子机制仍然未知，尽管CPT1C在去棕榈酰化GluA1中的假设作用已经被假设。在这里，我们探索了这种可能性，并表明CPT1C对AMPARs的影响可能是由于GluA1棕榈酰化状态的改变。基于硅分析，预测Ser 252、His 470和Asp 474是CPT1C棕榈酰硫酯酶（PTE）活性的催化三联体。当这些残基发生突变或PTE活性受到抑制时，CPT1C对AMPAR运输的影响被消除，从而验证了CPT1C催化三联体是负责AMPAR上PTE活性的。此外，CPT1C的组氨酸残基（His 470）对神经元中GluA1表面表达的增加至关重要，而H470A突变会损害CPT1C去棕榈酰化的催化活性。最后，我们发现CPT1C效应似乎是特异性的CPT1亚型，它只发生在内质网（ER）。这项工作为调节AMPAR生理的分子机制增加了另一个令人印象深刻的方面。
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.
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影响因子：
2.9
作者：
Krivov, Georgii G.;Shapovalov, Maxim V.;Dunbrack, Roland L., Jr.
通讯作者：
Dunbrack, Roland L., Jr.
影响因子：
4.1
作者：
Fraser, F;Corstorphine, CG;Zammit, VA
通讯作者：
Zammit, VA
影响因子：
14.8
作者：
Dekker, Frank J.;Rocks, Oliver;Waldmann, Herbert
通讯作者：
Waldmann, Herbert
影响因子：
4.1
作者：
Broadway, NM;Pease, RJ;Saggerson, ED
通讯作者：
Saggerson, ED
DOI：
10.1007/978-1-4939-3064-7_21
发表时间：
2016-01-01
期刊：
RECEPTOR AND ION CHANNEL DETECTION IN THE BRAIN: METHODS AND PROTOCOLS
影响因子：
--
作者：
Coombs, Ian D.;Soto, David
通讯作者：
Soto, David