scholarly journals LARGE, an intellectual disability-associated protein, regulates AMPA-type glutamate receptor trafficking and memory

2018 ◽  
Vol 115 (27) ◽  
pp. 7111-7116 ◽  
Author(s):  
Bo Am Seo ◽  
Taesup Cho ◽  
Daniel Z. Lee ◽  
Joong-jae Lee ◽  
Boyoung Lee ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Glutamate Receptor ◽  
Long Term Potentiation ◽  
Fine Tuning ◽  
Functional Study ◽  
Large Gene ◽  
Severe Intellectual Disability ◽  
Glutamate Receptor Trafficking ◽  
Proteomic Study ◽  
The Brain

Mutations in the human LARGE gene result in severe intellectual disability and muscular dystrophy. How LARGE mutation leads to intellectual disability, however, is unclear. In our proteomic study, LARGE was found to be a component of the AMPA-type glutamate receptor (AMPA-R) protein complex, a main player for learning and memory in the brain. Here, our functional study of LARGE showed that LARGE at the Golgi apparatus (Golgi) negatively controlled AMPA-R trafficking from the Golgi to the plasma membrane, leading to down-regulated surface and synaptic AMPA-R targeting. In LARGE knockdown mice, long-term potentiation (LTP) was occluded by synaptic AMPA-R overloading, resulting in impaired contextual fear memory. These findings indicate that the fine-tuning of AMPA-R trafficking by LARGE at the Golgi is critical for hippocampus-dependent memory in the brain. Our study thus provides insights into the pathophysiology underlying cognitive deficits in brain disorders associated with intellectual disability.

scholarly journals LARGE, an AMPA receptor interactor, plays a large role in long-term memory formation by driving homeostatic scaling-down

2017 ◽  
Author(s):  
Bo Am Seo ◽  
Taesup Cho ◽  
Daniel Z. Lee ◽  
Hwa Young Lee ◽  
Joong-Jae Lee ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Long Term Potentiation ◽  
Memory Formation ◽  
Fine Tuning ◽  
Functional Study ◽  
Long Term Memory ◽  
Term Memory ◽  
Scaling Down ◽  
The Brain

AbstractDynamic trafficking of AMPA-type glutamate receptor (AMPA-R) in neuronal cells is a key cellular mechanism for learning and memory in the brain, which is regulated by AMPA-R interacting proteins. LARGE, a protein associated with intellectual disability, was found to be a novel component of the AMPA-R protein complex in our proteomic study. Here, our functional study of LARGE showed that during homeostatic scaling-down, increased LARGE expression at the Golgi apparatus (Golgi) negatively controlled AMPA-R trafficking from the Golgi to the plasma membrane, leading to downregulated surface and synaptic AMPA-R targeting. In LARGE knockdown mice, long-term potentiation (LTP) was occluded by synaptic AMPA-R overloading, resulting in impaired long-term memory formation. These findings indicate that the fine-tuning of AMPA-R trafficking by LARGE at the Golgi is critical for memory stability in the brain. Our study thus provides novel insights into the pathophysiology of brain disorders associated with intellectual disability.

scholarly journals Metabotropic Glutamate Receptor Trafficking and its Role in Drug-Induced Neurobehavioral Plasticity

2021 ◽  
pp. 1-16
Author(s):  
Peter U. Hámor ◽  
Marek Schwendt
Keyword(s):  
Glutamate Receptor ◽  
Membrane Trafficking ◽  
Metabotropic Glutamate Receptor ◽  
Neuropsychiatric Disorders ◽  
Surface Expression ◽  
Receptor Trafficking ◽  
Fine Tuning ◽  
Cell Surface Expression ◽  
Metabotropic Glutamate ◽  
Glutamate Receptor Trafficking

Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system that guides developmental and experience-dependent changes in many cellular substrates and brain circuits, through the process collectively referred to as neurobehavioral plasticity. Regulation of cell surface expression and membrane trafficking of glutamate receptors represents an important mechanism that assures optimal excitatory transmission, and at the same time, also allows for fine-tuning neuronal responses to glutamate. On the other hand, there is growing evidence implicating dysregulated glutamate receptor trafficking in the pathophysiology of several neuropsychiatric disorders. This review provides up-to-date information on the molecular determinants regulating trafficking and surface expression of metabotropic glutamate (mGlu) receptors in the rodent and human brain and discusses the role of mGluR trafficking in maladaptive synaptic plasticity produced by addictive drugs. As substantial evidence links glutamatergic dysfunction to the progression and the severity of drug addiction, advances in our understanding of mGluR trafficking may provide opportunities for the development of novel pharmacotherapies of addiction and other neuropsychiatric disorders.

scholarly journals Ligand-directed two-step labeling to quantify neuronal glutamate receptor trafficking

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Kento Ojima ◽  
Kazuki Shiraiwa ◽  
Kyohei Soga ◽  
Tomohiro Doura ◽  
Mikiko Takato ◽  
...  
Keyword(s):  
Glutamate Receptors ◽  
Glutamate Receptor ◽  
Receptor Trafficking ◽  
Protein Labeling ◽  
Selective Labeling ◽  
Receptor Localization ◽  
Glutamate Receptor Trafficking ◽  
Versatile Tool ◽  
The Central Nervous System ◽  
Long Lifetime

AbstractThe regulation of glutamate receptor localization is critical for development and synaptic plasticity in the central nervous system. Conventional biochemical and molecular biological approaches have been widely used to analyze glutamate receptor trafficking, especially for α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate-type glutamate receptors (AMPARs). However, conflicting findings have been reported because of a lack of useful tools for analyzing endogenous AMPARs. Here, we develop a method for the rapid and selective labeling of AMPARs with chemical probes, by combining affinity-based protein labeling and bioorthogonal click chemistry under physiological temperature in culture medium. This method allows us to quantify AMPAR distribution and trafficking, which reveals some unique features of AMPARs, such as a long lifetime and a rapid recycling in neurons. This method is also successfully expanded to selectively label N-methyl-D-aspartate-type glutamate receptors. Thus, bioorthogonal two-step labeling may be a versatile tool for investigating the physiological and pathophysiological roles of glutamate receptors in neurons.

scholarly journals MiR-7 in Cancer Development

Biomedicines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 325
Author(s):  
Petra Korać ◽  
Mariastefania Antica ◽  
Maja Matulić
Keyword(s):  
Cell Fate ◽  
Dominant Role ◽  
Tumor Development ◽  
Mrna Translation ◽  
Cell Types ◽  
Fine Tuning ◽  
Non Coding Rna ◽  
Tumor Types ◽  
Different Cell Types ◽  
The Brain

MicroRNAs (miRNAs) are short non-coding RNA involved in the regulation of specific mRNA translation. They participate in cellular signaling circuits and can act as oncogenes in tumor development, so-called oncomirs, as well as tumor suppressors. miR-7 is an ancient miRNA involved in the fine-tuning of several signaling pathways, acting mainly as tumor suppressor. Through downregulation of PI3K and MAPK pathways, its dominant role is the suppression of proliferation and survival, stimulation of apoptosis and inhibition of migration. Besides these functions, it has numerous additional roles in the differentiation process of different cell types, protection from stress and chromatin remodulation. One of the most investigated tissues is the brain, where its downregulation is linked with glioblastoma cell proliferation. Its deregulation is found also in other tumor types, such as in liver, lung and pancreas. In some types of lung and oral carcinoma, it can act as oncomir. miR-7 roles in cell fate determination and maintenance of cell homeostasis are still to be discovered, as well as the possibilities of its use as a specific biotherapeutic.

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