Isom Lab News

Open postdoctoral positions in the Isom Lab!

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We are searching for postdoctoral fellows to work on our NIH-funded…

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

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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.

Dancing to a different tune: TANGO gives hope for Dravet syndrome

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This article was written by Professor David Henshall, Director of the FutureNeuro SFI Research Centre at the Royal College of Surgeons in Ireland.

Mask up, sleeve up, Go Blue!

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Dr. Luis Lopez-Santiago was excited to receive his first COVID-19 vaccination dose.

Allie Bouza leads Wolverine Pathways summer program in Pharmacology

Allie teaches seven budding scientists visiting from Ypsilanti and Southfield about bench research!

Congratulations to Chad Frasier, PhD (Isom Lab), 2017 AES Early Career Award Recipient

Novel mechanisms of SUDEP in SCN8A-EIEE13 patients, Postdoctoral Fellowship, an AES/Wishes for Elliott Fellowship supported by both Wishes for Elliott and AES.