Issues

Researchers worldwide are advancing our understanding of voltage-gated sodium channels, exploring their mechanisms, disease relevance, and potential as clinical targets in a rapidly evolving field. In this special issue, Abriel and Lampert bring together a collection of studies that exemplify the multidimensional progress in physiology, pharmacology, and structure-function analysis of voltage-gated sodium channels.

JGP study explains why mice lacking TRPM1 exhibit oscillatory firing of their retinal ganglion cells, and suggests that the same mechanism causes similar oscillations in other outer retinal diseases.

Pilagov and colleagues explore role of MyBP-C in regulation of the myosin SRX state in cardiac muscle.

Horie et al. show that TRPM1 deficiency in ON bipolar cells produces retinal ganglion cell oscillations in association with rod bipolar cell axon remodeling and reduced ON bipolar cell outputs, and may represent a shared circuit mechanism underlying pathological oscillations across different causes of outer retinal diseases.

We identify a peripheral PIP₂-binding site conserved across TRP channels using coarse-grained MD simulations. This site facilitates PIP₂ access to the primary binding site and may represent an alternative regulatory mechanism common to the TRP channel superfamily.

The role of the I–II linker in regulating voltage-dependent gating of Nav1.5 channels is not well understood. Deleting large sections of the linker did not affect gating. However, changes to the protein sequence did affect gating, showing how certain variants can alter channel function.

This work explores the evolutionary origins of the sodium leak channel NALCN and its ancillary subunits FAM155/Mid1, UNC79, and UNC80. We uncover ancient origins for these subunits in eukaryotes, and identify animals, fungi, and apusomonads as three distinct lineages possessing all four NALCN subunits.

In two individuals with small fiber neuropathy carrying the cosegregating variant c.197A>C; p.(Tyr66Ser) in SCN11A, we observed on/off-like axon hyperexcitability upon sine-wave stimulation, correlating with patch-clamp results of the Na_V1.9 channel variant.

Zangerl-Plessl et al. utilized MD simulations and revealed that PIP2 potentiated clockwise twisting motions in individual Kir2 channel cytoplasmic subunits, as well as concerted dynamics among the four subunits. These findings could partly explain the underlying mechanisms of cooperative channel gating.

We assessed skeletal muscle properties in GOF knock-in mouse models of Cantu Syndrome. In isolated myofibers there was enhanced Mg-nucleotide activation in SUR2 GOF, but not Kir6.1 GOF fibers. Isolated SUR2 GOF muscles showed enhanced fatiguing that was reversed by the KATP inhibitor glibenclamide.

Topical application of D2 receptor ligands modulates CSD propagation in a ligand- and time-dependent manner. Electrophysiological and immunohistochemical analyses, supported by computational modeling, reveal that dopaminergic signaling influences cortical excitability and CSD dynamics, offering new mechanistic insights into dopamine’s cortical role.

This study shows that hypoxia-induced SUMOylation and the disease-linked Kir2.1 mutation, R67Q, converge to impair channel function by destabilizing interactions with PIP₂. The findings support a two-hit model of Andersen-Tawil syndrome and identify the SUMO pathway as a potential therapeutic target.