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G protein-coupled receptors (GPCRs) constitute the largest family of membrane proteins and are important drug targets. The discovery of drugs targeting these receptors and their G protein signaling properties are based on assays mainly performed with modified receptors expressed in heterologous cells. However, GPCR responses may differ in their native environment. Here, by using highly sensitive G i/o sensors, we reveal specific properties of G i/o protein-mediated responses triggered by GABA B , α 2 adrenergic and cannabinoid CB1 receptors in primary neurons, different from those in heterologous cells. These include different profiles in the G i/o protein subtypes-mediated responses, and differences in the potencies of some ligands even at similar receptor expression levels. Altogether, our results show the importance of using biosensors compatible with primary cells for evaluating the activities of endogenous GPCRs in their native environment., (© 2024. The Author(s).)

Transition metal dichalcogenides, by virtue of their two-dimensional structures, could provide the largest active surface for reactions with minimal materials consumed, which has long been pursued in the design of ideal catalysts. Nevertheless, their structurally perfect basal planes are typically inert; their surface defects, such as under-coordinated atoms at the surfaces or edges, can instead serve as catalytically active centers. Here we show a reaction probability > 90 % for adsorbed methanol (CH 3 OH) on under-coordinated Pt sites at surface Te vacancies, produced with Ar + bombardment, on layered PtTe 2 - approximately 60 % of the methanol decompose to surface intermediates CH x O (x = 2, 3) and 35 % to CH x (x = 1, 2), and an ultimate production of gaseous molecular hydrogen, methane, water and formaldehyde. The characteristic reactivity is attributed to both the triangular positioning and varied degrees of oxidation of the under-coordinated Pt at Te vacancies., (© 2024. The Author(s).)

Near infrared energy remains untapped toward the maneuvering of entire solar spectrum harvesting for fulfilling the nuts and bolts of solar hydrogen production. We report the use of Au@Cu 7 S 4 yolk@shell nanocrystals as dual-plasmonic photocatalysts to achieve remarkable hydrogen production under visible and near infrared illumination. Ultrafast spectroscopic data reveal the prevalence of long-lived charge separation states for Au@Cu 7 S 4 under both visible and near infrared excitation. Combined with the advantageous features of yolk@shell nanostructures, Au@Cu 7 S 4 achieves a peak quantum yield of 9.4% at 500 nm and a record-breaking quantum yield of 7.3% at 2200 nm for hydrogen production in the absence of additional co-catalysts. The design of a sustainable visible- and near infrared-responsive photocatalytic system is expected to inspire further widespread applications in solar fuel generation. In this work, the feasibility of exploiting the localized surface plasmon resonance property of self-doped, nonstoichiometric semiconductor nanocrystals for the realization of wide-spectrum-driven photocatalysis is highlighted., (© 2024. The Author(s).)

G protein-coupled receptors (GPCRs) are important drug targets that mediate various signaling pathways by activating G proteins and engaging β-arrestin proteins. Despite its importance for the development of therapeutics with fewer side effects, the underlying mechanism that controls the balance between these signaling modes of GPCRs remains largely unclear. Here, we show that assembly into dimers and oligomers can largely influence the signaling mode of the platelet-activating factor receptor (PAFR). Single-particle analysis results show that PAFR can form oligomers at low densities through two possible dimer interfaces. Stabilization of PAFR oligomers through cross-linking increases G protein activity, and decreases β-arrestin recruitment and agonist-induced internalization significantly. Reciprocally, β-arrestin prevents PAFR oligomerization. Our results highlight a mechanism involved in the control of receptor signaling, and thereby provide important insights into the relationship between GPCR oligomerization and downstream signaling., (© 2022. The Author(s).)

Domestic ducks are raised for meat, eggs and feather down, and almost all varieties are descended from the Mallard (Anas platyrhynchos). Here, we report chromosome-level high-quality genome assemblies for meat and laying duck breeds, and the Mallard. Our new genomic databases contain annotations for thousands of new protein-coding genes and recover a major percentage of the presumed "missing genes" in birds. We obtain the entire genomic sequences for the C-type lectin (CTL) family members that regulate eggshell biomineralization. Our population and comparative genomics analyses provide more than 36 million sequence variants between duck populations. Furthermore, a mutant cell line allows confirmation of the predicted anti-adipogenic function of NR2F2 in the duck, and uncovered mutations specific to Pekin duck that potentially affect adipose deposition. Our study provides insights into avian evolution and the genetics of oviparity, and will be a rich resource for the future genetic improvement of commercial traits in the duck., (© 2021. The Author(s).)

Much hope in drug development comes from the discovery of positive allosteric modulators (PAM) that display target subtype selectivity and act by increasing agonist potency and efficacy. How such compounds can allosterically influence agonist action remains unclear. Metabotropic glutamate receptors (mGlu) are G protein-coupled receptors that represent promising targets for brain diseases, and for which PAMs acting in the transmembrane domain have been developed. Here, we explore the effect of a PAM on the structural dynamics of mGlu2 in optimized detergent micelles using single molecule FRET at submillisecond timescales. We show that glutamate only partially stabilizes the extracellular domains in the active state. Full activation is only observed in the presence of a PAM or the G i protein. Our results provide important insights on the role of allosteric modulators in mGlu activation, by stabilizing the active state of a receptor that is otherwise rapidly oscillating between active and inactive states., (© 2021. The Author(s).)

G protein-coupled receptors (GPCRs) can integrate extracellular signals via allosteric interactions within dimers and higher-order oligomers. However, the structural bases of these interactions remain unclear. Here, we use the GABA B receptor heterodimer as a model as it forms large complexes in the brain. It is subjected to genetic mutations mainly affecting transmembrane 6 (TM6) and involved in human diseases. By cross-linking, we identify the transmembrane interfaces involved in GABA B1 -GABA B2 , as well as GABA B1 -GABA B1 interactions. Our data are consistent with an oligomer made of a row of GABA B1 . We bring evidence that agonist activation induces a concerted rearrangement of the various interfaces. While the GB1-GB2 interface is proposed to involve TM5 in the inactive state, cross-linking of TM6s lead to constitutive activity. These data bring insight for our understanding of the allosteric interaction between GPCRs within oligomers.

Advanced electrocatalysts with low platinum content, high activity and durability for the oxygen reduction reaction can benefit the widespread commercial use of fuel cell technology. Here, we report a platinum-trimer decorated cobalt-palladium core-shell nanocatalyst with a low platinum loading of only 2.4 wt% for the use in alkaline fuel cell cathodes. This ternary catalyst shows a mass activity that is enhanced by a factor of 30.6 relative to a commercial platinum catalyst, which is attributed to the unique charge localization induced by platinum-trimer decoration. The high stability of the decorated trimers endows the catalyst with an outstanding durability, maintaining decent electrocatalytic activity with no degradation for more than 322,000 potential cycles in alkaline electrolyte. These findings are expected to be useful for surface engineering and design of advanced fuel cell catalysts with atomic-scale platinum decoration.

Peripheral neuropathic pain (PNP) is a debilitating and intractable chronic disease, for which sensitization of somatosensory neurons present in dorsal root ganglia that project to the dorsal spinal cord is a key physiopathological process. Here, we show that hematopoietic cells present at the nerve injury site express the cytokine FL, the ligand of fms-like tyrosine kinase 3 receptor (FLT3). FLT3 activation by intra-sciatic nerve injection of FL is sufficient to produce pain hypersensitivity, activate PNP-associated gene expression and generate short-term and long-term sensitization of sensory neurons. Nerve injury-induced PNP symptoms and associated-molecular changes were strongly altered in Flt3-deficient mice or reversed after neuronal FLT3 downregulation in wild-type mice. A first-in-class FLT3 negative allosteric modulator, discovered by structure-based in silico screening, strongly reduced nerve injury-induced sensory hypersensitivity, but had no effect on nociception in non-injured animals. Collectively, our data suggest a new and specific therapeutic approach for PNP.

Antibodies have enormous therapeutic and biotechnology potential. G protein-coupled receptors (GPCRs), the main targets in drug development, are of major interest in antibody development programs. Metabotropic glutamate receptors are dimeric GPCRs that can control synaptic activity in a multitude of ways. Here we identify llama nanobodies that specifically recognize mGlu2 receptors, among the eight subtypes of mGluR subunits. Among these nanobodies, DN10 and 13 are positive allosteric modulators (PAM) on homodimeric mGlu2, while DN10 displays also a significant partial agonist activity. DN10 and DN13 have no effect on mGlu2-3 and mGlu2-4 heterodimers. These PAMs enhance the inhibitory action of the orthosteric mGlu2/mGlu3 agonist, DCG-IV, at mossy fiber terminals in the CA3 region of hippocampal slices. DN13 also impairs contextual fear memory when injected in the CA3 region of hippocampal region. These data highlight the potential of developing antibodies with allosteric actions on GPCRs to better define their roles in vivo.

Efficient cell-to-cell communication relies on the accurate signalling of cell surface receptors. Understanding the molecular bases of their activation requires the characterization of the dynamic equilibrium between active and resting states. Here, we monitor, using single-molecule Förster resonance energy transfer, the kinetics of the reorientation of the extracellular ligand-binding domain of the metabotropic glutamate receptor (mGluR), a class C G-protein-coupled receptor. We demonstrate that most receptors oscillate between a resting- and an active-conformation on a sub-millisecond timescale. Interestingly, we demonstrate that differences in agonist efficacies stem from differing abilities to shift the conformational equilibrium towards the fully active state, rather than from the stabilization of alternative static conformations, which further highlights the dynamic nature of mGluRs and revises our understanding of receptor activation and allosteric modulation.