Neuronal ASIC channels mediate excitatory sodium currents in response to extracellular acidification. Lynagh et al. reveal the essential roles of pore-lining glutamates in ion conduction and selectivity for ASIC1a- and ASIC2a-containing channels.

Mammalian isoforms of mitochondrial VDAC have unique functional roles in vivo, but they all share similar β-barrel pore structures. Queralt-Martín et al. provide the first mechanistic insights into VDAC’s isoform-specific function by showing that VDAC3 exhibits unique properties when interacting with cytosolic proteins α-synuclein and tubulin.

Bohannon et al. show that polyunsaturated fatty acids (PUFAs) vary in their ability to activate cardiac IKs potassium channels depending on the pKa of the PUFA head group, allowing PUFAs to be tuned to treat long QT syndrome mutants with different disease severity.

The auxiliary proteins CaM and FHF bind to the C-terminal domain of voltage-gated sodium channels to limit the persistent inward currents associated with cardiac arrhythmias. Gade et al. reveal that CaM and FHF exert their effects by stabilizing an interaction between the channel’s C-terminal domain and III-IV linker region.

Molecular bases of pathogenic enhancement of Ca2+ release channel activities in RYR1 carrying disease-associated mutations at the N-terminal region were studied. Functional studies and MD simulation revealed that the interactions between domains have a strong correlation with channel activity.

Secondary active transport mechanisms often depict a limited number of states and transitions, although recent research suggests that alternative “leak” pathways are not always minor. Hussey et al. numerically simulate a fully unrestricted model for the bacterial transporter EmrE and demonstrate that highly efficient transport can be achieved despite the existence of multiple leak pathways.

CRAC channels contain a cluster of positively charged residues in the inner pore whose function is not understood. Here, we show that these positive charges promote pore opening by enhancing hydration of the hydrophobic gate located at the outer end of the pore.