Sun et al. show that the commonly used Ca_V3 T-type channel-selective antagonists, ML218 and Z944, modulate the activity of Ca_V1.4 L-type channels through a mechanism involving the dihydropyridine-binding site.

Nguyen et al. show that Arg-92 in GIRK2 is essential for PIP2-dependent gating, with substitutions causing structural rearrangements that disrupt G protein and alcohol activation—likely a conserved mechanism among inward rectifier potassium channels.

Lopez-Mateos et al.’s study demonstrates AlphaFold2’s potential to sample multiple states of human NaV channels. Additionally, NaV α-subunit interactions with β-subunits and calmodulin reshape NaV α-subunit conformational landscape. This study reveals the potential of deep learning methods to model structural diversity of ion channels.

KdpFABC is a unique potassium pump that combines channel-like selectivity with ATP-driven transport. Using simulations, X-ray scattering, and biochemical assays, this study shows that its inter-subunit tunnel is mainly water-filled and has a single stable potassium site. The findings challenge the idea of a continuous ion-wire and highlight a key barrier at the KdpA–KdpB interface.

Channel gating in cyclic nucleotide-binding domain (CNBD) channels has traditionally been described using allosteric models. This work by Lin and Chanda compares different gating models to account for the diverse gating phenotypes observed across the CNBD family, including those arising from targeted mutations and chimeragenesis.

This study describes a novel negative allosteric modulator that engages previously unexplored structural determinants in an allosteric binding site between NMDA receptor subunits, enabling new opportunities for structure-based design of subtype-selective NMDA receptor modulators.

The CTD of voltage-gated sodium channels influences many properties of the channel. Here, Akshay Sharma et al. show the differential effects of CTD missense mutations of cardiac sodium channel activation, inactivation, persistent current, and accessory protein modulation and suggest the structural bases for these mutational effects.