Development and characterization of the mode-of-action of inhibitory and agonist peptides targeting the voltage-gated sodium channel SCN1B beta-subunit.

Autor: Williams ZJ; Fralin Biomedical Research Institute, Virginia Polytechnic University, Roanoke, VA, United States., Alvarez-Laviada A; Department of Myocardial Function, Imperial College London, London, United Kingdom., Hoagland D; Fralin Biomedical Research Institute, Virginia Polytechnic University, Roanoke, VA, United States., Jourdan LJ; Fralin Biomedical Research Institute, Virginia Polytechnic University, Roanoke, VA, United States., Poelzing S; Fralin Biomedical Research Institute, Virginia Polytechnic University, Roanoke, VA, United States; School of Medicine, Virgina Polytechnic University, Roanoke, VA, United States; Department of Biomedical Engineering and Mechanics, Virginia Polytechnic University, Roanoke, VA, United States., Gorelik J; Department of Myocardial Function, Imperial College London, London, United Kingdom., Gourdie RG; Fralin Biomedical Research Institute, Virginia Polytechnic University, Roanoke, VA, United States; School of Medicine, Virgina Polytechnic University, Roanoke, VA, United States; Department of Biomedical Engineering and Mechanics, Virginia Polytechnic University, Roanoke, VA, United States. Electronic address: gourdier@vtc.vt.edu.
Jazyk: angličtina
Zdroj: Journal of molecular and cellular cardiology [J Mol Cell Cardiol] 2024 Sep; Vol. 194, pp. 32-45. Date of Electronic Publication: 2024 Jun 26.
DOI: 10.1016/j.yjmcc.2024.06.008
Abstrakt: Cardiac arrhythmia treatment is a clinical challenge necessitating safer and more effective therapies. Recent studies have highlighted the role of the perinexus, an intercalated disc nanodomain enriched in voltage-gated sodium channels including both Na v 1.5 and β1 subunits, adjacent to gap junctions. These findings offer insights into action potential conduction in the heart. A 19-amino acid SCN1B (β1/β1B) mimetic peptide, βadp1, disrupts VGSC beta subunit-mediated adhesion in cardiac perinexii, inducing arrhythmogenic changes. We aimed to explore βadp1's mechanism and develop novel SCN1B mimetic peptides affecting β1-mediated adhesion. Using patch clamp assays in neonatal rat cardiomyocytes and electric cell substrate impedance sensing (ECIS) in β1-expressing cells, we observed βadp1 maintained inhibitory effects for up to 5 h. A shorter peptide (LQLEED) based on the carboxyl-terminus of βadp1 mimicked this inhibitory effect, while dimeric peptides containing repeated LQLEED sequences paradoxically promoted intercellular adhesion over longer time courses. Moreover, we found a link between these peptides and β1-regulated intramembrane proteolysis (RIP) - a signaling pathway effecting gene transcription including that of VGSC subunits. βadp1 increased RIP continuously over 48 h, while dimeric agonists acutely boosted RIP for up to 6 h. In the presence of DAPT, an RIP inhibitor, βadp1's effects on ECIS-measured intercellular adhesion was reduced, suggesting a relationship between RIP and the peptide's inhibitory action. In conclusion, novel SCN1B (β1/β1B) mimetic peptides are reported with the potential to modulate intercellular VGSC β1-mediated adhesion, potentially through β1 RIP. These findings suggest a path towards the development of anti-arrhythmic drugs targeting the perinexus.
Competing Interests: Declaration of competing interest Authors Zachary J. Williams, Daniel Hoagland, L. Jane Jourdan, Steven Poelzing, and Robert G. Gourdie report a PCT patent application submitted to USPTO Mar. 1st 2023 (PCT/US2023/063525) on the β1 mimetic dimeric peptides that are the subject of this manuscript.
(Copyright © 2024. Published by Elsevier Ltd.)
Databáze: MEDLINE
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