Computational study of non-conductive selectivity filter conformations and C-type inactivation in a voltage-dependent 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.
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.
Evidence that toxin resistance in poison birds and frogs is not rooted in sodium channel mutations and may rely on “toxin sponge” proteins
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.
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.
Conformations of voltage-sensing domain III differentially define NaV channel closed- and open-state inactivation
Angsutararux et al. propose that the voltage-sensing domains of repeats III and IV of NaV 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.