Issues

JGP study provides new mechanistic insights into the cholesterol-dependent modulation of pain sensation by DRG neurons.

Schmidt and Kopec discuss how Lopez-Mateos et al. use AlphaFold 2 to generate structural ensembles of voltage-gated sodium channels across different conformations. They highlight that auxiliary subunits reshape these ensembles, while cautioning that predicted conformations represent testable hypotheses, not thermodynamic populations.

This review explores the role of cMyBP-C post-translational modifications in health and disease. During cardiovascular disease, oxidative stress may drive the inverse relationship between phosphorylation and S-glutathionylation of cMyBP-C, identifying new therapeutic opportunities.

Behringer et al. show how coarse-grained computational methods uncover long range mechanical connectivities in HCN channels. Complementary to high-resolution cryoEM structures these computational methods provide insights into the communication between ligand binding- and voltage sensing domains for allosteric regulation of these channels.

Cholesterol in cell membranes plays a key role in controlling how pain-sensing neurons respond. Our study shows that distinct cholesterol pools—OMD-associated and freely accessible cholesterol—differently influence HCN ion channels, which regulate nerve excitability. Changes in these pools after nerve injury alter pacemaker channel behavior, offering insights into pain mechanisms and potential treatments.

Within islets of Langerhans, gap junctions synchronize pulsatile [Ca²⁺] and insulin release. Subpopulations of insulin-producing β-cells that show unique dynamics can drive synchronized [Ca²⁺] and insulin release, and their loss in diabetes may drive islet dysfunction. Levitt et al. investigate how loss of gap junctions under diabetogenic environments and their protection influence these subpopulations.

Navs exhibit high Li⁺ selectivity similar to Na⁺. We present the first prokaryotic Nav mutant that conducts Li⁺ with approximately twice the efficiency of Na⁺. Electrophysiological and crystallographic analyses suggest atomic determinants that facilitate Li⁺ permeation through the ion pore.

A neuronal nicotinic acetylcholine receptor from Xenopus tropicalis frogs possesses exquisite sensitivity to acetylcholine due to a single amino acid substitution in the α4 M3 domain possibly produced by RNA editing.

He et al. demonstrate that ion channels from photoreceptors in the retina are very sensitive to photodynamic modification mediated by singlet oxygen, ¹O₂, the molecular oxygen in electronically excited states. This study provides essential insights into the underlying mechanism of ¹O₂-mediated protein modification.

Hoover Browne et al. report that deleting the P-zone domains A164–167 from titin in a novel mouse model reveals their critical role in muscle function and thick filament structure, including maintaining titin’s α and β conformations.

Beat-locked cytosolic and mitochondrial ATP transients in SA node myocytes sort into high-gain, low-gain, or consumption-dominant modes aligned with superior–inferior vascular–mitochondrial gradients. This energetic hierarchy lets high-gain cells set fast rates, while low-gain/dip cells stabilize slow rhythms, broadening operating range but capping maximal bandwidth.

Hussey et al. evaluate the impact of disease-causing mutations in calmodulin on multiple voltage-gated calcium channels. The study demonstrates a disruption of the calcium/calmodulin-dependent regulation Ca_V1.3 and Ca_V2.1 channels by calmodulin variants, expanding the potential molecular targets in the pathogenesis of calmodulinopathies.

Tonotopicity is canonically universal in the mammalian cochlea. We previously found that the low-frequency guinea pig organ of Corti is not tonotopic. We hypothesized that tonotopicity was preserved at the basilar membrane. Neither structure is tonotopic in the apex. Also, nonlinearities change in type and extent throughout the apex.

Mutations affecting the skeletal muscle sodium channel Na_v1.4 may result in a range of disorders. A novel missense mutation is described to be found in a patient with weakness provoked by physical activity. Electrophysiology is used to detect a plethora of effects on the activation and inactivation processes.