ON THE COVER
A detailed computational model of striated muscle elucidates how mutations and drugs may alter twitch timing. The spatially explicit model simulates myosin motors connected within a compliant, contractile lattice, complete with thin filament regulation and varying mutation penetrance. The model yields data used to train classifiers. Image © Asencio et al., 2023. See https://doi.org/10.1085/jgp.202213291.
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Tweaking the catalytic efficiency of the CFTR ion channel
CFTR, unique among ABC transporters, evolved to function as an ion channel in part by optimizing the stability of the open state.
Sensing its own permeant ion: KCNQ1 channel inhibition by external K+
External potassium inhibits KCNQ1 channel through a mechanism involving increased occupancy of the filter S0 site by K+o.
Mechanism of external K+ sensitivity of KCNQ1 channels
Occupation of the uppermost ion-binding site of the selectivity filter of K+ channels by external K+ promotes channel activity. Such a phenomenon is not observed in KCNQ1 voltage-gated channels, allowing a deeper understanding of their conduction and permeability mechanism.
Microscopic mechanism of PIEZO1 activation by pressure-induced membrane stretch
Membrane stretch activates mechanosensitive PIEZO1 channels, but how this stimulus modulates microscopic open and shut states to increase open probability is unknown. Here, Wijerathne et al. investigate this mechanism using single channel dwell time analysis and Markov-chain modeling.
Similar voltage-sensor movement in spHCN channels can cause closing, opening, or inactivation
We show here that a similar voltage-sensor movement in mutant hyperpolarization-activated cyclic nucleotide-gated (HCN) channels can lead to more closing or more opening depending on the cAMP concentration, suggesting that voltage sensor-to-gate coupling is easily altered in HCN channels.
Differential regulation of cardiac sodium channels by intracellular fibroblast growth factors
Intracellular fibroblast growth factors (iFGF) regulate voltage-gated sodium (NaV) channel expression and gating. Using a mouse model and heterologous expression in Xenopus oocytes, we describe mechanisms of how iFGF alters NaV channel activation and inactivation.
A cooperative knock-on mechanism underpins Ca2+-selective cation permeation in TRPV channels
TRPV5 and TRPV6 are unique among TRP channels due to their high Ca2+ selectivity, while most other members of this ion channel family do not select for a specific cation type. Ives et al. used biomolecular simulations and in silico electrophysiology to determine the mechanism underlying this unusual Ca2+ selectivity.
Blockade of TRPV channels by intracellular spermine
This manuscript reports discovery of voltage-dependent inhibition of TRPV channels by intracellular polyamines and develops a kinetic model of this process. Polyamines are inhibitors of each TRPV sub-type.
Depolarization-induced bursts of miniature synaptic currents in individual synapses of developing cerebellum
Spontaneous glutamatergic postsynaptic currents recorded in developing cerebellar interneurons are enhanced by presynaptic depolarization. In response to depolarization, they are organized in bursts. Le Guellec, Gomez et al. propose that bursts signal simultaneous pre- and postsynaptic calcium elevation in single synapses, and that they help synapse formation or stabilization.
Thin filament regulation of cardiac muscle power output: Implications for targets to improve human failing hearts
Phosphorylation of the N-terminal region of cardiac troponin I was found to regulate myofilament power output, and this posttranslational modification can be leveraged to increase power output in myofilaments from human failing hearts.
Machine learning meets Monte Carlo methods for models of muscle’s molecular machinery to classify mutations
Asencio et al. use a spatially explicit model to simulate muscle twitch forces representing cardiac disease states. Using this dataset, they apply dimension reduction techniques and machine learning methods to build a novel classifier of perturbation type from twitch timing.
BK channels of five different subunit combinations underlie the de novo KCNMA1 G375R channelopathy
A heterozygous BK channelopathy G375R/WT expresses five different types of channels differing in voltage activation and conductance. Four of the five are pathogenic.
Mechanosensitive channel MscS is critical for termination of the bacterial hypoosmotic permeability response
The kinetics of hypotonic osmolyte release from E. coli is analyzed in conjunction with bacterial survival. It is shown that MscL, the high-threshold “emergency release valve,” rescues bacteria from down-shocks only in the presence of MscS, MscK, or other low-threshold channels that are necessary to pacify MscL at the end of the release phase.
Letters to the Editor
About hysteresis in Shaker: A note on Cowgill and Chanda
This letter proposes an alternative explanation to the work published by Cowgill and Chanda on the nature of hysteresis in the voltage-gated, potassium-selective channel Shaker.
About hysteresis in Shaker: Response to note by Villalba-Galea
Our response points out the deficiencies in the alternative explanation proposed by Villalba-Galea to account for our findings on hysteresis (or lack thereof) in steady state charge–voltage curves of Shaker potassium channel.