JEWJITSU PEPTIDES: Research roundup on cardiac sodium channels and amyloid peptide aggregation

This study used automated patch-clamp, human Nav isoform profiling, human iPSC-derived cardiomyocytes, adult ventricular myocytes, isolated hearts and in vivo experiments to compare INaL inducers. The authors report that the commonly used ATX-II predominantly activates TTX-resistant Nav1.5 and lacks isoform selectivity when applied without caution. By contrast, the scorpion peptide AaH-II more selectively and potently enhances late sodium current via tetrodotoxin-sensitive (TTX-S) Nav isoforms. In cellular models, TTX-S INaL produced action-potential prolongation and abnormal Ca2+ handling, and in isolated-heart and in vivo preparations selective TTX-S activation caused conduction abnormalities, QT prolongation and ventricular proarrhythmic events. Nanomolar tetrodotoxin prevented these effects while sparing Nav1.5. The authors present AaH-II as a selective pharmacological tool to probe TTX-S INaL and conclude that TTX-S channels can generate arrhythmogenic late Na+ current independently of Nav1.5. Limitations noted by reading the report include the need for broader validation across models and careful interpretation when extrapolating pharmacology toward therapeutic strategies.

The REST2 simulation study examined hexamers of the Aβ25-35 fragment in wild-type, N27A (reported less toxic) and M35A (reported more toxic) variants. Simulations predominantly sampled distinct β-barrel arrangements: N27A hexamers favored four-stranded barrels, wild-type favored six-stranded barrels, and M35A favored five-stranded barrels, with hydrophobic contacts in the I30–G33 region driving assembly. Analyses of hydrogen bonds and binding energies suggested that both β-barrel disassembly propensity and N-terminal hydration (G25–K28) correlate with the toxicity trend N27A < WT < M35A observed in prior work. The authors propose two structural mechanisms: that disassembly propensity governs transition to cytotoxic oligomers, and that exposure of the N-terminal domain modulates peptide–membrane interactions. They suggest targeting hydrophobic core residues or N-terminal contacts to reduce oligomer toxicity; these proposals arise from in silico results and the study itself implies experimental validation is required.

Using coarse-grained molecular dynamics, the third study explored how Ca2+ reshapes aggregation of the Aβ16-22 model fragment on a mixed bilayer (30% anionic PS, 70% PC). The authors report that Ca2+ screens membrane surface charge and reduces hydrophobic packing defects, delaying initial peptide adsorption and favoring formation of larger aggregates in solution that later adsorb as preformed assemblies. Once adsorbed, PS–Ca2+–PS ionic bridges condensed PS around peptide aggregates and reduced lipid lateral mobility, producing larger, less ordered aggregates with shallower insertion and hydrophobic residues exposed to solvent, a structural signature the authors link to seeding-active species. The simulation results align with Western blot evidence of enhanced aggregation in the presence of Ca2+. Limitations include use of a short model fragment, coarse-grained representation and a specific membrane composition, so further atomistic and experimental studies would be needed to generalize the mechanism.