Ahern et al. show that the absence of Rad increases peak L-type calcium influx independently of β-adrenergic receptor signaling. This increased peak current is homeostatically balanced by channel inactivation, allowing enhanced contraction without action potential prolongation. The loss of Rad is a potential therapeutic target for safe positive inotropic support.

Moise et al. develop a finite element model of the intercalated disk (ID) that takes into account the nanoscale structure. Incorporating these details in a cardiac tissue model predicts that alterations in ID structure can affect electrical conduction in the heart.

Lopez-Redondo et al. use cryo-EM and molecular dynamics to evaluate the effects of Zn2+ binding on the conformation and dynamics of the zinc/proton antiporter YiiP. Removal of Zn2+ leads to enhanced conformational dynamics and causes a transition to an intermediate state in the transport cycle.

Zhao et al. leverage the analysis of local conformational changes in a mutant Hv1 channel to inform the design of new inhibitors. These arginine mimics have improved interaction with the voltage-sensing domain and inhibit the wild-type channel with higher strength than guanidine derivatives.

Zhao and colleagues use the Hv1 channel to study drugs that modulate channel activity by binding to the voltage-sensing domain (VSD). They describe a new compound that interacts with a known and a new site in distinct conformations and thus suggests new strategies to identify VSD-binding compounds.

Han et al. study the effect of primary cardiac hypertrophy on cardiac mechano-energetics. Using isolated cardiac tissues, they show that despite impaired contractile performance, cardiac mechanical efficiency is preserved in hypertrophic hearts.

Passive force generated in titin plays an important role in maintaining sarcomere structure. In this paper, van der Pijl et al. describe a mechanism by which muscle ankyrin repeat protein 1 (MARP1) locks titin to the thin filament to increase passive force.