Issues

Hearts of hibernating mammals continue to beat at near 0°C thanks to continued excitability. Several members of a minor group of voltage-gated Na channels in the heart are found to contain a mutation unique to hibernators. Molecular details of this mutation may help to explain the continued activity of the heart in the cold.

Gaitán-Peñas et al. show that DCPIB inhibition of VRAC does not depend on a single residue but relies on adaptable binding modes combining electrostatic and hydrophobic interactions. Their findings reveal electrostatic complementarity as the main determinant of high-affinity block, providing a framework for rational design of improved VRAC inhibitors.

Na/K pump α1 subunit variants cause several disease phenotypes. Here, we show that all variants known to cause hypomagnesemia and seizures carry aberrant leak currents and have both reduced function and reduced plasmalemma expression. The cryo-EM structure of variant W931R suggests that the leaking ions may permeate through the protein/lipid interface.

The conductive state of the TMEM16A channel has not been determined, making it difficult to understand how the channel operates. Here, we use molecular simulations to show that the 1PBC-bound structure opens upon inhibitor removal. We found a hydrophobic network between TM3 and TM4 that stabilizes the open conformation and confirmed its importance experimentally.

The contraction of skeletal muscles is turned on by Ca²⁺ released from the cellular store by RyR channels in a quasi-crystalline array, half of which only have contacts with neighbor RyRs. Rios and Pizarro’s model assumes these channels to be controlled allosterically by their neighbors and matches quantitatively observations of Ca²⁺ release gathered over decades.

We developed a kinetic framework for the major membrane-current components in Paramecium. The framework integrates late-component, leak, and inward Ca²⁺ currents, including Ca²⁺-dependent inactivation and slow recovery. It reproduces graded membrane responses under the present recording conditions.

Bysack and Raghuraman show specific lipid–protein interactions mediate the cholesterol-induced reorganization of the slide helix in membranes during cholesterol-dependent regulation of KirBac1.1. Importantly, they hypothesize that the slide helix movement might function as a lipid-sensitive “conformational-switch” controlling KirBac1.1 gating.

Bioelectrical signaling is important in many small structures, such as bacteria, viruses, and intracellular vesicles. The dynamics in small structures are strongly affected by stochastic gating of single ion channels. Howell et al. provide a framework for predicting and interpreting bioelectrical dynamics in small structures.

Sodium channel antagonist bulleyaconitine and agonist aconitine bind in the pore-domain fenestration I/II and stabilize the open activation gate. Aconitine transiently chelates passing sodium ions, while protonated bulleyaconitine blocks the permeation.

KCNC1 encodes the potassium channel subunit K_V3.1 critical for high-frequency neuronal firing. Variants cause a spectrum of neurological disorders. While the recurrent p.Thr399Met variant shows complete loss of function alone, co-expression with wild-type subunits reveals a “dominant-positive” gain of function, highlighting complex potassium channel subunit interactions.

In this study, Crowther and colleagues report new disease-causing variants in the TASK-1 and TASK-3 potassium channels responsible for two different neurodevelopmental disorders. They also examine the structural and functional properties of these variants and examine their effects when incorporated into heteromeric TASK-1/TASK-3 channels.

Lammens et al. show how an auxiliary β1 subunit tunes the activity of the human Na⁺ channel Na_V1.6, a key regulator of electrical signaling in neurons. By identifying one extracellular residue required for this effect, the study links channel structure to mechanisms that shape neuronal excitability.

Along with membrane potential and respiration, mitochondrial matrix volume is a critical parameter that is linked to physiological and pathological states. Here, we present an assay for detection of the dynamic changes in mitochondrial matrix volume in living cells. This approach will become very useful for many researchers working in the field of cell biology.

This Review highlights how structurally simple prokaryotic potassium channels have consistently informed mechanisms in complex eukaryotic channels. By integrating structural and functional insights, the authors show that bacterial models remain powerful tools for generating hypotheses about regulatory principles across channel families.

Feng discusses how a hydrophobic interaction network between TM3 and TM4 stabilizes an ion-conductive conformation of the TMEM16A chloride channel. Comparison with TMEM16 lipid scramblases suggests that functional diversity across the TMEM16 family may arise from differences in the stability of TM3–TM4 interactions and the resulting distinct TM4 rearrangements.

Couplons are large multi-protein clusters consisting of Ca_V1.1 and RyR1 channels that connect SR and transverse tubulus in skeletal muscle cells and permit voltage-controlled Ca²⁺ release. Rios and Pizarro (2026) simulate allosteric interactions within the couplon using Markov chain modelling to successfully describe many characteristics of whole-cell and microdomain Ca²⁺ signals.