Issues

JGP study reveals that the auxiliary Ca_vβ₃ subunit regulates the cardiac calcium channel Ca_v1.2 by modulating the two-step activation of VSD II.

Lotti et al. report a new subtype-selective allosteric inhibitor with improved potency and elucidate its mechanism of inhibition.

Rios reviews the relevance for physiology and pathophysiology of the synchronous gating of sarco-endoplasmic reticulum Ca²⁺ release channels, reported in bilayer reconstitution experiments. While he finds clear evidence of allosteric interchannel interactions, their physiological relevance remains plausible and unproven.

This study describes a novel negative allosteric modulator that engages previously unexplored structural determinants in an allosteric binding site between NMDA receptor subunits, enabling new opportunities for structure-based design of subtype-selective NMDA receptor modulators.

Premature stop variants in myosin-binding protein H-like prevent sarcomere incorporation of the translated protein regardless of the location of the premature stop along the protein. Overexpression of truncating variants causes contractile defects in neonatal rat cardiomyocytes.

Combining voltage-clamp fluorometry, kinetic modeling, and molecular dynamics simulation, we show that the auxiliary β-subunit remodels only voltage sensor II and its allosteric contribution to channel opening upon the translocation of two charges before reaching full activation.

The CTD of voltage-gated sodium channels influences many properties of the channel. Here, Akshay Sharma et al. show the differential effects of CTD missense mutations of cardiac sodium channel activation, inactivation, persistent current, and accessory protein modulation and suggest the structural bases for these mutational effects.

Jaque-Fernandez et al. show that depolarization of zebrafish skeletal muscle fibers evokes a Mn²⁺ quenching signal that does not result from store-operated Ca²⁺ entry but from a displacement of Mn²⁺ accumulated on intracellular Ca²⁺ buffers by the increase in intracellular Ca²⁺.

Zhou et al. ask whether distinct β subunit isoforms coassemble in BK channel complexes or segregate into different complexes. Taking advantage of differences in β2- and β3a-mediated inactivation, macroscopic currents, single channels, and biochemical tests unambiguously show that ternary β2:β3:α subunit ternary complexes form, consistent with a trinomial model of random mixing of β subunits.

KdpFABC is a unique potassium pump that combines channel-like selectivity with ATP-driven transport. Using simulations, X-ray scattering, and biochemical assays, this study shows that its inter-subunit tunnel is mainly water-filled and has a single stable potassium site. The findings challenge the idea of a continuous ion-wire and highlight a key barrier at the KdpA–KdpB interface.

Nguyen et al. show that Arg-92 in GIRK2 is essential for PIP2-dependent gating, with substitutions causing structural rearrangements that disrupt G protein and alcohol activation—likely a conserved mechanism among inward rectifier potassium channels.

Channel gating in cyclic nucleotide-binding domain (CNBD) channels has traditionally been described using allosteric models. This work by Lin and Chanda compares different gating models to account for the diverse gating phenotypes observed across the CNBD family, including those arising from targeted mutations and chimeragenesis.

Ex vivo muscle fiber cultures help scientists study skeletal muscle disease mechanisms, but long-term use causes structural decline and loss-of-function. Vonk, Esen et al. report that 3D culture environments preserve muscle fiber health and contractility better than 2D systems, offering an improved model for drug screening and testing genetic interventions.

Zhou et al. introduce a novel optogenetic approach to control ion channel activity using a photocaged lysine. Combined with VSP, the method provides new insights into PI(4,5)P₂-dependent ion channels and offers a promising tool for in-depth analysis of PI(4,5)P₂-regulated ion transport proteins.