Allard appraises recent studies investigating the pathological mechanism of hypokalemic periodic paralysis mutations.
Jones et al. provide commentary on the intricate crosstalk between ion transporters that goes awry in long QT arrhythmia.
Lam and Chesler highlight the recent discovery of a G protein–coupled receptor involved in detecting mechanical shear stress.
Milestone in Physiology
Falzone et al. interpret the mechanisms underlying the activity of TMEM16 family members from recent structural and functional work.
Members of the claudin family form tight junctions between adjacent epithelial and endothelial cells. Samanta et al. build an atomic model of claudin-15 using molecular dynamics simulations and conclude that four claudin-15 molecules each contribute an aspartic acid residue to form a selectivity filter.
Mutations in ATP-sensitive K+ channels can cause permanent neonatal diabetes mellitus, and patients with some mutations become practically insensitive to the common antidiabetic drug sulphonylurea. Ramu et al. identify a 54-residue protein (SpTx-1) that inhibits human wild-type and sulphonylurea-insensitive mutant KATP channels with a Kd of 15 nM.
External K+ dependence of strong inward rectifier K+ channel conductance is caused not by K+ but by competitive pore blockade by external Na+
The conductance of the strong inward rectifier K+ channel depends on the “square root” of the extracellular K+ concentration. The present study shows that this physiologically important phenomenon is caused by a channel blockade by extracellular Na+, which is competitive with extracellular K+.
Tetrodotoxin-sensitive Navs contribute to early and delayed afterdepolarizations in long QT arrhythmia models
Neuronal Na+ channels contribute to catecholaminergic polymorphic ventricular tachycardia in the heart, but their role in other types of arrhythmias is unknown. Koleske et al. show that they contribute to early and delayed afterdepolarizations common to long QT, catecholaminergic polymorphic ventricular tachycardia, and overlap phenotypes.
Intracellular and extracellular loops of LRRC8 are essential for volume-regulated anion channel function
Volume-regulated anion channels (VRACs) comprise the essential LRRC8A subunit plus one or more LRRC8 paralogs. By engineering chimeras that form homomeric channels, Yamada and Strange show that the intracellular and first extracellular loops of LRRC8 are essential for VRAC structure and function.
Replacing voltage sensor arginines with citrulline provides mechanistic insight into charge versus shape
Activation of voltage-gated channels results from the outward movement of arginine residues on the S4 segments. Infield et al. use in vivo nonsense suppression to replace Shaker's S4 arginine residues with citrulline and reveal that a positive charge is required on R4 for voltage-dependent deactivation.
Voltage-gated ion channels are subject to posttranslational modification, including glycosylation. Lopez-Rodriguez and Holmgren show that, in Shaker KV channels, deglycosylation influences voltage sensing and open–closed transitions but not binding of ligands to the protein.
Methods and Approaches
The mitochondrial calcium uniporter is a Ca2+ channel that has been hard to characterize electrophysiologically. Tsai and Tsai establish a method that permits efficient electrophysiological recordings of the human uniporter in Xenopus oocytes and demonstrate characteristic uniporter behaviour.