Issues

FGF14 encodes a sodium channel accessory subunit. Mutations in Fgf14 are linked to spinocerebellar ataxia type 27. Fgf14 deletion in mouse Purkinje neurons causes reduced excitability. We show here that targeted Fgf14 deletion in mouse CA1 pyramidal neurons causes increased firing, revealing cell-type specific effects.

In cardiac muscle, leiomodin-2 and tropomodulin-1 compete for binding thin filaments to control their length. We showed that mutations that lower leiomodin-2’s affinity for tropomyosin weaken its ability to displace tropomodulin-1. This highlights the critical role of the tropomyosin-binding site in the competition.

Obscurin deletion in mice is linked to compensated dilated cardiomyopathy, reduced sarcoplasmic reticulum volume, T-tubule alterations, altered E-C coupling, impaired response to inotropic agents, and increased propensity to arrhythmias.

Jo et al. use the Nav1.8 inhibitors suzetrigine, A-887826, and LTGO-33 to show differences in the kinetics with which the compounds unbind from depolarized channels and rebind to resting state channels, explaining reverse use dependence under physiological conditions seen with A-887826 but not suzetrigine or LTGO-33.

To store and preserve muscle function, glycerol is often used, but its effect on passive properties is unclear. Muscles stored in glycerol showed increased passive stress that persisted after thin filament removal, indicating a titin-specific mechanism. Glycerol storage should be avoided in passive stiffness studies.

The development of analgesic drugs targeting sodium channels Na_V1.7 and Na_V1.8 is described. FDA approval of the Na_V1.8 antagonist suzetrigine presages an exciting new era in analgesic treatment with the drug alone, or in combination with other types of analgesic.