Evolutionarily Established Palmitoylation-Dependent Regulatory Mechanisms of the Vertebrate Glutamatergic Synapse and Diseases Caused by Their Disruption

Hayashi, Takashi

doi:10.3389/fnmol.2021.796912

Cited by 5 publications

(5 citation statements)

References 36 publications

(41 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, biochemical results of reduced GluA1 palmitoylation and increased synaptic expression of GluA1 in PSD of the amygdala (Supplementary Fig. 7A , B), which should enhance AMPA receptor synaptic retention as well as synaptic plasticity [ 26 , 27 , 32 , 34 ], explain behavioral alterations well. Cue (tone)-dependent (auditory) fear conditioning is mediated by the potentiation of glutamatergic synaptic transmission in the lateral amygdala [ 66 , 67 ].…”

Section: Discussionmentioning

confidence: 99%

“…We have previously reported that palmitoylation regulates the synaptic expression of AMPA receptors [ 16 , 26 – 30 ]. All mammalian AMPA receptor subunits, GluA1-4, are palmitoylated at their C-terminal conserved region in an activity-dependent manner [ 24 , 26 , 31 , 32 ]. Palmitoylation inhibits GluA1 interaction with the postsynaptic 4.1N protein, which stabilizes synaptic AMPA receptor expression in long-term potentiation (LTP) [ 26 , 27 , 33 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Prolonged contextual fear memory in AMPA receptor palmitoylation-deficient mice

Oota-Ishigaki

Takao

Yamada

et al. 2022

Neuropsychopharmacol.

Self Cite

View full text Add to dashboard Cite

Long-lasting fear-related disorders depend on the excessive retention of traumatic fear memory. We previously showed that the palmitoylation-dependent removal of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors prevents hyperexcitation-based epileptic seizures and that AMPA receptor palmitoylation maintains neural network stability. In this study, AMPA receptor subunit GluA1 C-terminal palmitoylation-deficient (GluA1C811S) mice were subjected to comprehensive behavioral battery tests to further examine whether the mutation causes other neuropsychiatric disease-like symptoms. The behavioral analyses revealed that palmitoylation-deficiency in GluA1 is responsible for characteristic prolonged contextual fear memory formation, whereas GluA1C811S mice showed no impairment of anxiety-like behaviors at the basal state. In addition, fear generalization gradually increased in these mutant mice without affecting their cued fear. Furthermore, fear extinction training by repeated exposure of mice to conditioned stimuli had little effect on GluA1C811S mice, which is in line with augmentation of synaptic transmission in pyramidal neurons in the basolateral amygdala. In contrast, locomotion, sociability, depression-related behaviors, and spatial learning and memory were unaffected by the GluA1 non-palmitoylation mutation. These results indicate that impairment of AMPA receptor palmitoylation specifically causes posttraumatic stress disorder (PTSD)-like symptoms.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Prolonged contextual fear memory in AMPA receptor palmitoylation-deficient mice

Oota-Ishigaki

Takao

Yamada

et al. 2022

Neuropsychopharmacol.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Many neuronal receptors and ion channels are regulated by their reversible modification of the palmitoylation and depalmitoylation cycle ( Kang et al, 2008 ; Shipston, 2011 ; Borroni et al, 2016 ; Hayashi, 2021a ). In various modifications evolutionarily established in the vertebrate glutamatergic excitatory synapses, the most probable mechanism that forces AMPA receptors to translocate into lipid rafts microdomain is the palmitoylation of the receptors themselves ( Hayashi et al, 2005 ; Matt et al, 2019 ; Hayashi, 2021a , b ).…”

Section: Discussionmentioning

confidence: 99%

Membrane lipid rafts are required for AMPA receptor tyrosine phosphorylation

Hayashi

2022

Front. Synaptic Neurosci.

Self Cite

View full text Add to dashboard Cite

Membrane lipid rafts are sphingolipids and cholesterol-enriched membrane microdomains, which form a center for the interaction or assembly of palmitoylated signaling molecules, including Src family non-receptor type protein tyrosine kinases. Lipid rafts abundantly exist in neurons and function in the maintenance of synapses. Excitatory synaptic strength is largely controlled by the surface expression of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors in the mammalian brain. AMPA receptor endocytosis from the synaptic surface is regulated by phosphorylation of the GluA2 subunit at tyrosine 876 by Src family kinases. Here, I revealed that tyrosine phosphorylated GluA2 is concentrated in the lipid rafts fraction. Furthermore, stimulation-induced upregulation of GluA2 tyrosine phosphorylation is disrupted by the treatment of neurons with a cholesterol-depleting compound, filipin III. These results indicate the importance of lipid rafts as enzymatic reactive sites for AMPA receptor tyrosine phosphorylation and subsequent AMPA receptor internalization from the synaptic surface.

show abstract

“…Studying protein palmitoylation using lower model organisms like Saccharomyces cerevisiae , Caenorhabditis elegans , Drosophila melanogaster and Mus musculus has immense potential to provide critical insights due to the conserved role of palmitoylation and associated pathological processes contributing to neurodegeneration ( Hayashi, 2021 ). Studies have identified 7 PATs in Saccharomyces cerevisiae , 15 in Caenorhabditis elegans , 22 in Drosophila melanogaster and 24 in Mus musculus ( Bannan et al, 2008 ; Edmonds and Morgan, 2014 ; Zaballa and van der Goot, 2018 ).…”

Section: Putting Together the Ancestral Puzzle Of Palmitoylation: Les...mentioning

confidence: 99%

Lost in traffic: consequences of altered palmitoylation in neurodegeneration

et al. 2023

View full text Add to dashboard Cite

One of the first molecular events in neurodegenerative diseases, regardless of etiology, is protein mislocalization. Protein mislocalization in neurons is often linked to proteostasis deficiencies leading to the build-up of misfolded proteins and/or organelles that contributes to cellular toxicity and cell death. By understanding how proteins mislocalize in neurons, we can develop novel therapeutics that target the earliest stages of neurodegeneration. A critical mechanism regulating protein localization and proteostasis in neurons is the protein-lipid modification S-acylation, the reversible addition of fatty acids to cysteine residues. S-acylation is more commonly referred to as S-palmitoylation or simply palmitoylation, which is the addition of the 16-carbon fatty acid palmitate to proteins. Like phosphorylation, palmitoylation is highly dynamic and tightly regulated by writers (i.e., palmitoyl acyltransferases) and erasers (i.e., depalmitoylating enzymes). The hydrophobic fatty acid anchors proteins to membranes; thus, the reversibility allows proteins to be re-directed to and from membranes based on local signaling factors. This is particularly important in the nervous system, where axons (output projections) can be meters long. Any disturbance in protein trafficking can have dire consequences. Indeed, many proteins involved in neurodegenerative diseases are palmitoylated, and many more have been identified in palmitoyl-proteomic studies. It follows that palmitoyl acyl transferase enzymes have also been implicated in numerous diseases. In addition, palmitoylation can work in concert with cellular mechanisms, like autophagy, to affect cell health and protein modifications, such as acetylation, nitrosylation, and ubiquitination, to affect protein function and turnover. Limited studies have further revealed a sexually dimorphic pattern of protein palmitoylation. Therefore, palmitoylation can have wide-reaching consequences in neurodegenerative diseases.

show abstract

Evolutionarily Established Palmitoylation-Dependent Regulatory Mechanisms of the Vertebrate Glutamatergic Synapse and Diseases Caused by Their Disruption

Cited by 5 publications

References 36 publications

Prolonged contextual fear memory in AMPA receptor palmitoylation-deficient mice

Prolonged contextual fear memory in AMPA receptor palmitoylation-deficient mice

Membrane lipid rafts are required for AMPA receptor tyrosine phosphorylation

Lost in traffic: consequences of altered palmitoylation in neurodegeneration

Contact Info

Product

Resources

About