Issues

JGP modeling study suggests that selectivity filter constriction is a plausible mechanism for C-type inactivation of the Shaker voltage-gated potassium channel.

Li et al. carry out molecular dynamics simulations of the K⁺ channels Shaker and KcsA to test whether a structural constriction of the non-conductive selectivity filter is a universal mechanism of C-type inactivation in K⁺ channels.

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.

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.

Some poisonous animals produce toxins that affect Na⁺ channel function yet avoid autointoxication. Abderemane-Ali et al. show that resistance by Pitohui birds and Phyllobates frogs to their own toxins may be mediated not by mutations in their channels, but by toxin-sequestering “sponge” proteins.

Vouga et al. show that the opioid receptor agonist loperamide is an inhibitor of large-conductance Ca²⁺-activated K⁺ (BK) channels that acts as a state-dependent pore blocker. Loperamide may exert its therapeutic effect partly by inhibiting potassium efflux in the intestine.

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.

Angsutararux et al. propose that the voltage-sensing domains of repeats III and IV of Na_V channels regulate state-dependent inactivation by modulating the conformation and affinity of the IFMT motif found in the linker between the III and IV repeats.