Issues

We present an interactive model of lysosomal ion homeostasis that remains robust during different biologically relevant stresses. Our simulations indicate that lysosomal Ca²⁺ depletion couples with organellar deacidification triggered by either increased proton leakage or vATPase inhibition, with potential involvement of TMEM165 inhibition.

Using a combined biophysical and computational approaches, we determined how morphological, intrinsic, and extrinsic factors shape spiking activity in vivo. The computational model was fitted to spiking experimental data, and the variations in the resulting parameters were used to predict the altered spiking activity. Our methodology is likely applicable to other systems and species.

Lukyanenko et al. show that dysferlin’s N-terminal C2 domain, DysfC2A, regulates skeletal muscle Ca²⁺ signaling and membrane repair specifically. DysfC2A does not target triad junctions, whereas the homologous but inactive PKCαC2 domain does. DysfC2A targeted to triad junctions as a PKCαC2 chimera is as active as dysferlin itself, suggesting possible use for dysferlin gene replacement.

This study reveals that a KCNE4 polymorphism differentially regulates Kv1.3 activity. This work highlights how the size and charge of a single residue within an anionic cluster critically shape the function of Kv1.3.

In their work, Feher et al. examine the molecular mechanism of NZ-58, a novel hHv1 inhibitor. Their findings suggest that it binds to the upper gating triad containing countercharges D112 and D185, leading to a “kinetic trapping” mechanism of inhibition.

Dry eye disease is very common worldwide and often resistant to available therapeutics. Verma et al. developed a computational model linking tear production, evaporation, and drainage with ocular surface epithelial transport to predict tear film thickness and osmolality. The model was used to evaluate current therapies for dry eye disease and propose novel cellular targets.

Ponissery Saidu et al. address how the two olfactory transduction channels, the CNG channel and the Cl⁻ channel TMEM16B, are modulated by cholesterol. The channels are affected differentially: the Cl⁻ current amplitude and CNG channel ligand sensitivity are altered, which further depends on whether the channels are heterologously expressed or from native cells.

Lorenzo-Ceballos et al. show that long-term inactivation (LTI) of Na_V1.2 channels mediated by A-isoforms of different FGF homologues (FGF11–FGF14) differ both in intrinsic rates of onset and rates of recovery from LTI. Furthermore, FGF’s allosterically mediate slowing of fast inactivation. Specific effects of each FGF-A result in homologue-specific use-dependent changes in Na_V availability.

Using specific gene subunit knockout mice, Scala et al. show that K_ATP channels formed exclusively of SUR2/Kir6.2 cause delayed fatigue and development of unstimulated force in isolated EDL skeletal muscles, suggesting similar contractile deficits will be present in ABCC9-dependent intellectual disability myopathy syndrome and KCNJ11-dependent neonatal diabetes.

This is a Review that covers the main advances in our understanding of fast sodium channel inactivation since the original work of Hodgkin and Huxley to the present era of structural biology.

Schuldiner recounts the decades-long journey of VMAT research, bridging foundational bioenergetics with recent high-resolution structural breakthroughs. This retrospective highlights the role of serendipity and “optimistic ignorance” in discovery, providing a comprehensive framework for understanding the essential mechanisms of neurotransmitter storage and their significant therapeutic potential.

Hussey et al. show dysregulation of neuronal Cav1.3 and Cav2.1 Ca²⁺ channels as a potential pathogenic mechanism contributing to neurological symptoms associated with calmodulinopathies.

Rainbow and Barrett-Jolley discuss Scala et al., who combined genetic and pharmacological approaches to demonstrate that Kir6.2/SUR2-containing K_ATP potassium ion channels are the functionally relevant isoform that modulate contractile behavior of fast-twitch muscle during fatigue.

JGP study shows that, in the absence of full-length dysferlin, its C2A domain alone can support normal Ca2⁺ signaling and sarcolemma repair, suggesting that it could be used in gene replacement therapies.