Identification of BiP as a CB Receptor-Interacting Protein That Fine-Tunes Cannabinoid Signaling in the Mouse Brain.

Cannabinoids, the bioactive constituents of cannabis, exert a wide array of effects on the brain by engaging Type 1 cannabinoid receptor (CBR). Accruing evidence supports that cannabinoid action relies on context-dependent factors, such as the biological characteristics of the target cell, suggesting that cell population-intrinsic molecular cues modulate CBR-dependent signaling. Here, by using a yeast two-hybrid-based high-throughput screening, we identified BiP as a potential CBR-interacting protein.

Structure reveals the activation mechanism of the MC4 receptor to initiate satiation signaling.

Obesity is a global epidemic that causes morbidity and impaired quality of life. The melanocortin receptor 4 (MC4R) is at the crux of appetite, energy homeostasis, and body-weight control in the central nervous system and is a prime target for anti-obesity drugs. Here, we present the cryo-electron microscopy (cryo-EM) structure of the human MC4R-G signaling complex bound to the agonist setmelanotide, a cyclic peptide recently approved for the treatment of obesity.

Modulation of dopamine D receptors via histamine H receptors is a novel therapeutic target for Huntington's disease.

Early Huntington's disease (HD) include over-activation of dopamine D receptors (DR), producing an imbalance in dopaminergic neurotransmission and cell death. To reduce DR over-activation, we present a strategy based on targeting complexes of DR and histamine H receptors (HR). Using an HD mouse striatal cell model and HD mouse organotypic brain slices we found that DR-induced cell death signaling and neuronal degeneration, are mitigated by an HR antagonist.

null C57BL/6N mice develop cardiomyopathy, whereas null C57BL/6J mice do not.

The C57BL/6J and C57BL/6N mice have well-documented phenotypic and genotypic differences, including the infamous nicotinamide nucleotide transhydrogenase () null mutation in the C57BL/6J substrain, which has been linked to cardiovascular traits in mice and cardiomyopathy in humans. To assess whether loss alone causes a cardiovascular phenotype, we investigated the C57BL/6N, C57BL/6J mice and a C57BL/6J-BAC transgenic rescuing NNT expression, at 3, 12, and 18 mo. We identified a modest dilated cardiomyopathy in the C57BL/6N mice, absent in the two B6J substrains.

Continuing challenges in targeting oligomeric GPCR-based drugs.

This chapter will focus on the therapeutic potential of oligomeric GPCR structures. We will discuss the history of these complexes and their connection with treatment. We will highlight several examples from the literature of complexes of therapeutic or theranostic opportunity.

Site-Specific Encoding of Photoactivity in Antibodies Enables Light-Mediated Antibody-Antigen Binding on Live Cells.

Antibodies have found applications in several fields, including, medicine, diagnostics, and nanotechnology, yet methods to modulate antibody-antigen binding using an external agent remain limited. Here, we have developed photoactive antibody fragments by genetic site-specific replacement of single tyrosine residues with photocaged tyrosine, in an antibody fragment, 7D12. A simple and robust assay is adopted to evaluate the light-mediated binding of 7D12 mutants to its target, epidermal growth factor receptor (EGFR), on the surface of cancer cells.

Design and development of stapled transmembrane peptides that disrupt the activity of G-protein-coupled receptor oligomers.

Membrane proteins can associate into larger complexes. Examples include receptor tyrosine complexes, ion channels, transporters, and G protein-coupled receptors (GPCRs). For the latter, there is abundant evidence indicating that GPCRs assemble into complexes, through both homo- and heterodimerization.

A Positive Allosteric Modulator of the Serotonin 5-HT Receptor for Obesity.

The 5-HTR agonist lorcaserin, clinically approved for the treatment of obesity, causes important side effects mainly related to subtype selectivity. In the search for 5-HTR allosteric modulators as safer antiobesity drugs, a chemical library from Vivia Biotech was screened using ExviTech platform. Structural modifications of identified hit VA240 in synthesized analogues 6-41 afforded compound 11 (N-[(1-benzyl-1H-indol-3-yl)methyl]pyridin-3-amine, VA012), which exhibited dose-dependent enhancement of serotonin efficacy, no significant off-target activities, and low binding competition with serotonin or other orthosteric ligands.

A new serotonin 5-HT receptor antagonist with procognitive activity - Importance of a halogen bond interaction to stabilize the binding.

Serotonin 5-HT receptor has been proposed as a promising therapeutic target for cognition enhancement though the development of new antagonists is still needed to validate these molecules as a drug class for the treatment of Alzheimer's disease and other pathologies associated with memory deficiency. As part of our efforts to target the 5-HT receptor, new benzimidazole-based compounds have been designed and synthesized. Site-directed mutagenesis and homology models show the importance of a halogen bond interaction between a chlorine atom of the new class of 5-HT receptor antagonists identified herein and a backbone carbonyl group in transmembrane domain 4.

Singular Location and Signaling Profile of Adenosine A-Cannabinoid CB Receptor Heteromers in the Dorsal Striatum.

The dorsal striatum is a key node for many neurobiological processes such as motor activity, cognitive functions, and affective processes. The proper functioning of striatal neurons relies critically on metabotropic receptors. Specifically, the main adenosine and endocannabinoid receptors present in the striatum, ie, adenosine A receptor (AR) and cannabinoid CB receptor (CBR), are of pivotal importance in the control of neuronal excitability.