RIP at the Synapse and the Role of Intracellular Domains in Neurons

Lee, Yan Jun; Ch’ng, Toh Hean

doi:10.1007/s12017-019-08556-4

Cited by 6 publications

(8 citation statements)

References 256 publications

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“…In addition to their nuclear functions, some ICDs play local roles at their site of cleavage (33). To test whether acute application of the b1-ICD could modulate sodium current directly, we applied a synthetic b1-ICD peptide (β1183-218) through the patch pipet during whole cell voltage clamp recording of HEK-hNav1.5 cells.…”

Section: β1-icd Overexpression In Heterologous Cells Leads To Differementioning

confidence: 99%

“…Finally, experiments to identify b1-ICD nuclear binding partners will be critical.Despite the identification of a growing list of RIP substrates, the factors that initiate RIP in specific cell types and subcellular domains are poorly understood. Neuronal activity and ligand binding have been shown to activate RIP at the synapse(33), but little is known about the initiation of RIP in heart. Our previous work showed that pretreatment with gsecretase inhibitors blocked b1-b1 trans homophilic cell adhesion mediated neurite outgrowth(43), consistent with the idea that b1 binding to other b1 subunits on adjacent cells may initiate RIP.…”

mentioning

confidence: 99%

“…In ventricular myocytes, b1-b1 trans homophilic adhesion at the intercalated disk may provide a similar environment for RIP activation(18). Substrate posttranslational modification, such as ubiquitination and palmitoylation, and specific subcellular localization/co-compartmentalization have been shown to be critical factors in regulating BACE and g-secretase cleavage(33,44). While our previous work has shown that b1 subunits are post-translationally modified by glycosylation, tyrosine phosphorylation(45,46), and palmitoylation (47), we have not yet investigated ubiquitination.…”

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confidence: 99%

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Sodium channel β1 subunits participate in regulated intramembrane proteolysis-excitation coupling

Bouza¹,

Edokobi²,

Hodges³

et al. 2021

JCI Insight

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Loss-of-function (LOF) variants in SCN1B, encoding voltage-gated sodium channel β1 subunits, are linked to human diseases with high risk of sudden death, including developmental and epileptic encephalopathy and cardiac arrhythmia. β1 Subunits modulate the cell-surface localization, gating, and kinetics of sodium channel pore-forming α subunits. They also participate in cell-cell and cell-matrix adhesion, resulting in intracellular signal transduction, promotion of cell migration, calcium handling, and regulation of cell morphology. Here, we investigated regulated intramembrane proteolysis (RIP) of β1 by BACE1 and γ-secretase and show that β1 subunits are substrates for sequential RIP by BACE1 and γ-secretase, resulting in the generation of a soluble intracellular domain (ICD) that is translocated to the nucleus. Using RNA sequencing, we identified a subset of genes that are downregulated by β1-ICD overexpression in heterologous cells but upregulated in Scn1b -null cardiac tissue, which lacks β1-ICD signaling, suggesting that the β1-ICD may normally function as a molecular brake on gene transcription in vivo. We propose that human disease variants resulting in SCN1B LOF cause transcriptional dysregulation that contributes to altered excitability. Moreover, these results provide important insights into the mechanism of SCN1B -linked channelopathies, adding RIP-excitation coupling to the multifunctionality of sodium channel β1 subunits.

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Section: β1-icd Overexpression In Heterologous Cells Leads To Differementioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Sodium channel β1 subunits participate in regulated intramembrane proteolysis-excitation coupling

Bouza¹,

Edokobi²,

Hodges³

et al. 2021

JCI Insight

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“…In some in vitro studies it has been shown that this compound is a powerful scavenger of hydroxyl radicals, hypochlorous acid, and peroxynitrite that can act as an antioxidant and cytoprotective and have a good penetration of the BBB. The authors also reported that ergothioneine protects against the damage induced by 7KC in brain endothelial cells [ 281 , 282 ].…”

Section: Antioxidants As Neuroprotectors In Patients Infected With Covid-19mentioning

confidence: 99%

Use of Antioxidants for the Neuro-Therapeutic Management of COVID-19

et al. 2021

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Coronavirus Disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is an emergent infectious disease that has caused millions of deaths throughout the world. COVID-19 infection’s main symptoms are fever, cough, fatigue, and neurological manifestations such as headache, myalgias, anosmia, ageusia, impaired consciousness, seizures, and even neuromuscular junctions’ disorders. In addition, it is known that this disease causes a series of systemic complications such as adverse respiratory distress syndrome, cardiac injury, acute kidney injury, and liver dysfunction. Due to the neurological symptoms associated with COVID-19, damage in the central nervous system has been suggested as well as the neuroinvasive potential of SARS-CoV-2. It is known that CoV infections are associated with an inflammation process related to the imbalance of the antioxidant system; cellular changes caused by oxidative stress contribute to brain tissue damage. Although anti-COVID-19 vaccines are under development, there is no specific treatment for COVID-19 and its clinical manifestations and complications; only supportive treatments with immunomodulators, anti-vascular endothelial growth factors, modulating drugs, statins, or nutritional supplements have been used. In the present work, we analyzed the potential of antioxidants as adjuvants for the treatment of COVID-19 and specifically their possible role in preventing or decreasing the neurological manifestations and neurological complications present in the disease.

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“…Synaptic activity can also lead to the proteolysis of synaptic intramembrane proteins, liberating peptides that signal to the nucleus (reviewed by Ref. [42]). This has been shown to be the case with the low-density lipoprotein receptor-related protein 8 (LRP8).…”

Section: Specificity That Emerges From the Synapsementioning

confidence: 99%

Mechanisms that communicate features of neuronal activity to the genome

Heinz

Bloodgood

2020

Current Opinion in Neurobiology

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Stimulus-driven gene expression is a ubiquitous feature of biological systems, allowing cells and organisms to adapt their function in a stimulus-driven manner. Neurons exhibit complex and heterogeneous activity-dependent gene expression, but many of the canonical mechanisms that transduce electrical activity into gene regulation are promiscuous and convergent. We discuss literature that describes mechanisms that drive activity-dependent gene expression with a focus on those that allow the nucleus to decode complex stimulus-features into appropriate transcriptional programs.

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RIP at the Synapse and the Role of Intracellular Domains in Neurons

Cited by 6 publications

References 256 publications

Sodium channel β1 subunits participate in regulated intramembrane proteolysis-excitation coupling

Sodium channel β1 subunits participate in regulated intramembrane proteolysis-excitation coupling

Use of Antioxidants for the Neuro-Therapeutic Management of COVID-19

Mechanisms that communicate features of neuronal activity to the genome

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