Loss of crossbridge inhibition drives pathological cardiac hypertrophy in patients harboring the TPM1 E192K mutation
Sewanan et al. studied a mutation to cardiac tropomyosin that causes hypertrophic cardiomyopathy. Computational models, in vitro experiments, and patient-specific engineered heart tissues suggest that this mutation triggers hypertrophy by allowing excess residual contractile activity.
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.
L-type channel inactivation balances the increased peak calcium current due to absence of Rad in cardiomyocytes
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.