Volume 31 Issue 4, April 2024

The identification of sodium and potassium currents as underlying action potential propagation, more than 70 years ago, opened a new avenue of research into the role of ion channels. In this Comment, we present our personal perspectives of the field, from the identification of Shaker as a potential potassium channel to the mechanistic insights available to us today.

G protein-coupled receptors (GPCRs) with no known endogenous ligand are termed orphans. Deorphanization of a GPCR involves identifying the ligand, which can be a painstaking exercise. In this Comment, we discuss the challenges in the process, its role in drug discovery and alternative approaches to characterizing orphan GPCRs.

Pregnancy loss is common in humans, but maternal genetic factors modulating its incidence are largely unknown. In a meta-analysis of genome-wide association studies, researchers identified a genetic variant that seems to increase risk of pregnancy loss by dysregulating meiotic recombination between homologous chromosomes during egg formation.

In this Perspective, the author describes the recent progress in understanding solute carrier (SLC) biology and discusses the roles of new families of atypical SLCs.

Structures of complete extracellular receptor assemblies mediated by the pro-inflammatory cytokines IL-12 and IL-23 reveal key commonalities and diverse features, with only IL-12 juxtaposing receptor domains proximal to the cell membrane.

Drugs with partial activity at the serotonin 3 receptors (5-HT₃R) are suited to normalize serotonin response in treating irritable bowel syndrome. Felt et al. demonstrate the mechanism of partial agonism in 5-HT_3AR using cryo-EM.

The authors present the structures of chemokine receptor CXCR3 complexed with agonists CXCL11, PS372424 and VUF11222 and antagonist SCH546738, providing a basis for the ligand recognition and activation mechanism of CXCR3.

MRP4 is an ATP-binding cassette transporter that transports prostanoids, a group of signaling molecules. The authors use cryo-EM to visualize the transport cycle and characterize its substrate selectivity.

Structural and biochemical studies show PU.1 facilitates C/EBPa binding to the CX3CR1 nucleosome by interacting with histone H2A and shifting the DNA position, leading to unwrapping of nucleosomal DNA and opening of the H1-condensed nucleosome array.

This study reveals the mechanism by which protons gate a CLC-type Cl⁻/H⁺ exchanger. The authors show that pH-dependent concerted structural rearrangements open the H⁺ pathway, which allosterically enables the Cl⁻ pore opening and ion exchange.

Here the authors determined structures of the mitochondrial ATP synthase at pH 6, in four distinct conformations. The structures represent intermediates in the reaction cycle of the enzyme and provide insights into its elastic coupling mechanism.

It is unknown how GPR161, an orphan receptor involved in Hedgehog signaling, is activated. This study identifies a sterol that promotes GPR161-driven cAMP signaling but shows that cAMP is dispensable for Hedgehog pathway repression.

Using cryo-EM, authors reveal the structure and activation mechanism of GPR156, a class C orphan GPCR implicated in sound detection. They find that GPR156 is a transducer for phospholipid signaling and provide insights into the basis for its constitutive activation.

A calcium ion binding site, hidden in the highly conserved gate of the synaptic AMPA-type ionotropic glutamate receptor, reveals upon gating and controls ion transport across the membrane, providing new mechanistic insights on ion permeation.

The authors report the structures of human CHT1 in the outward-open, inward-occluded and inward-open states, reveal the mechanism of HC-3 inhibition and choline recognition and elucidate the regulatory role of the intracellular helix IH1.

A variant predicted to affect chromosome alignment in meiosis associates with intrachromosomal positioning of recombination and increases risk of detectable pregnancy loss by 22%, likely through missegregation of chromosomes.

Kalienkova et al. use cryo-electron microscopy to capture 3D structures of a neuropeptide-gated DEG/ENaC ion channel in resting and ligand-bound states, detailing the mechanism by which peptides activate these excitatory ion channels.