Yamada et al. show that the prototypical LRRC8/VRAC inhibitor DCPIB stabilizes an inactivated channel state through coordinated interactions spanning extracellular, transmembrane, and N-terminal channel domains. Their findings define key determinants of state-dependent VRAC inhibition and provide a mechanistic framework for developing more potent and selective VRAC inhibitors.

K_ATP channels link a cell’s metabolic state to its electrical excitability through the binding of ADP/ATP to three classes of nucleotide-binding site. Rubio et al. synthesize and characterize a fluorescent ATP derivative to probe the activity of these sites.

Heart rate is controlled, in part, by the opening and closing of the ion channel HCN4. Recent work describes two ER-resident protein modulators of HCN4 that can either inhibit or potentiate channel function. Here, Blecker and colleagues describe the functionally relevant domains of both the channel and its potentiator IRAG.

AMPA receptors are glutamate receptors specific to bilaterian animals with complex nervous systems. Wang et al. investigated the biophysical function, pharmacology, and kinetics of AMPA receptors from diverse bilaterians, uncovering convergent evolution on functional hallmarks, such as heteromerization and channel properties, throughout the AMPA receptor family.

Using molecular dynamics, computational electrophysiology, and single-channel recordings, Arcario et al. identify a cryptic extracellular lateral fenestration in the pentameric ligand-gated ion channel, ELIC, that becomes the dominant cation conduction pathway. Expansion of this pathway is required to reproduce experimental conductance, revealing a revised mechanism of ion permeation in cation-selective pentameric ligand-gated ion channels.

Many clinically used drugs block cardiac hERG potassium channels yet also enhance current under some conditions. Docken, Marquis et al. combine kinetic modeling, atomistic simulations, and voltage-clamp experiments to test the hypothesis that the antiarrhythmic drug nifekalant opens hERG gates while blocking, revealing a mechanism that may reduce arrhythmia risk.

In the cardiomyocytes of male two-hit mice, both increased passive sarcomere stiffness and diastolic crossbridge activity represent potential therapeutic targets for reducing cardiomyocyte diastolic stiffness; whereas in females, cardiomyocyte diastolic stiffness is predominantly driven by elevated passive sarcomere stiffness.