Ligand-induced conformational changes in the β1-adrenergic receptor revealed by hydrogen-deuterium exchange mass spectrometry.

G Protein Coupled Receptors (GPCRs) constitute the largest family of signalling proteins responsible for translating extracellular stimuli into intracellular functions. They play crucial roles in numerous physiological processes and are major targets for drug discovery. Dysregulation of GPCRs is implicated in various diseases, making understanding their structural dynamics critical for therapeutic development.

Probe dependence and biased potentiation of metabotropic glutamate receptor 5 is mediated by differential ligand interactions in the common allosteric binding site.

The metabotropic glutamate receptor 5 (mGlu) is a promising therapeutic target for multiple CNS disorders. Recent mGlu drug discovery has focused on targeting binding sites within the mGlu 7-transmembrane domain (7TM) that are topographically distinct from that of the endogenous ligand. mGlu primarily couples to G proteins leading to mobilization of intracellular Ca (iCa), but also activates iCa independent signaling pathways, with biased agonism/modulation operative for multiple positive allosteric modulator (PAM) and PAM-agonist chemotypes.

Differential contribution of metabotropic glutamate receptor 5 common allosteric binding site residues to biased allosteric agonism.

Allosteric modulators of metabotropic glutamate receptor subtype 5 (mGlu) represent an attractive therapeutic strategy for multiple CNS disorders. Chemically distinct mGlu positive allosteric modulators (PAMs) that interact with a common binding site can demonstrate biased allosteric agonism relative to the orthosteric agonist, DHPG, when comparing activity in signaling assays such as IP accumulation, ERK1/2 phosphorylation (pERK1/2) and iCa mobilization. However, the structural basis for such biased agonism is not well understood.

Metabotropic glutamate receptor 5 (mGlu )-positive allosteric modulators differentially induce or potentiate desensitization of mGlu signaling in recombinant cells and neurons.

Allosteric modulators of metabotropic glutamate receptor 5 (mGlu ) are a promising therapeutic strategy for a number of neurological disorders. Multiple mGlu -positive allosteric modulator (PAM) chemotypes have been discovered that act as either pure PAMs or as PAM-agonists in recombinant and native cells. While these compounds have been tested in paradigms of receptor activation, their effects on receptor regulatory processes are largely unknown.

Kinetic and system bias as drivers of metabotropic glutamate receptor 5 allosteric modulator pharmacology.

Allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGlu) have been proposed as potential therapies for various CNS disorders. These ligands bind to sites distinct from the orthosteric (or endogenous) ligand, often with improved subtype selectivity and spatio-temporal control over receptor responses. We recently revealed that mGlu allosteric agonists and positive allosteric modulators exhibit biased agonism and/or modulation.

Ambient temperature modulates the effects of the Prader-Willi syndrome candidate gene Snord116 on energy homeostasis.

Germline deletion of the Prader-Willi syndrome (PWS) candidate gene Snord116 in mice leads to some classical symptoms of human PWS, notably reductions in body weight, linear growth and bone mass. However, Snord116 deficient mice (Snord116) do not develop an obese phenotype despite their increased food intake and the underlying mechanism for that is unknown. We tested the phenotypes of germline Snord116 as well as neuropeptide Y (NPY) neuron specific Snord116/NPY mice at 30°C, the thermoneutral temperature of mice, and compared these to previous reports studies conducted at normal room temperature.

Biased allosteric agonism and modulation of metabotropic glutamate receptor 5: Implications for optimizing preclinical neuroscience drug discovery.

Allosteric modulators, that exhibit no intrinsic agonist activity, offer the advantage of spatial and temporal fine-tuning of endogenous agonist activity, allowing the potential for increased selectivity, reduced adverse effects and improved clinical outcomes. Some allosteric ligands can differentially activate and/or modulate distinct signaling pathways arising from the same receptor, phenomena referred to as 'biased agonism' and 'biased modulation'. Emerging evidence for CNS disorders with glutamatergic dysfunction suggests the metabotropic glutamate receptor subtype 5 (mGlu) is a promising target.

Metabotropic glutamate receptor subtype 5: molecular pharmacology, allosteric modulation and stimulus bias.

The metabotropic glutamate receptor subtype 5 (mGlu5 ) is a family C GPCR that has been implicated in various neuronal processes and, consequently, in several CNS disorders. Over the past few decades, GPCR-based drug discovery, including that for mGlu5 receptors, has turned considerable attention to targeting allosteric binding sites. Modulation of endogenous agonists by allosteric ligands offers the advantages of spatial and temporal fine-tuning of receptor activity, increased selectivity and reduced adverse effects with the potential to elicit improved clinical outcomes.

Mutation analysis of the hamartin gene using denaturing high performance liquid chromatography.

Denaturing high performance liquid chromatography (DHPLC) is a novel high-capacity technique for gene mutation scanning. We have assessed the sensitivity and specificity of this method for analysis of the full coding sequence of the hamartin (TSC1) gene in 20 tuberous sclerosis patients, whose TSC1 genes previously had been studied by single strand conformation polymorphism analysis and protein truncation assay. All eight sequence variants previously identified were adequately detected by DHPLC.