scholarly journals CB1 Cannabinoid Receptor Signaling and Biased Signaling

Molecules ◽  
2021 ◽  
Vol 26 (17) ◽  
pp. 5413
Author(s):  
Luciana M. Leo ◽  
Mary E. Abood
Keyword(s):  
Adverse Effects ◽  
G Protein ◽  
Conformational Changes ◽  
Cannabinoid Receptor ◽  
Therapeutic Potential ◽  
Receptor Activation ◽  
Cb1 Receptor ◽  
Cb1 Cannabinoid Receptor ◽  
Biased Signaling ◽  
G Protein Coupled

The CB1 cannabinoid receptor is a G-protein coupled receptor highly expressed throughout the central nervous system that is a promising target for the treatment of various disorders, including anxiety, pain, and neurodegeneration. Despite the wide therapeutic potential of CB1, the development of drug candidates is hindered by adverse effects, rapid tolerance development, and abuse potential. Ligands that produce biased signaling—the preferential activation of a signaling transducer in detriment of another—have been proposed as a strategy to dissociate therapeutic and adverse effects for a variety of G-protein coupled receptors. However, biased signaling at the CB1 receptor is poorly understood due to a lack of strongly biased agonists. Here, we review studies that have investigated the biased signaling profile of classical cannabinoid agonists and allosteric ligands, searching for a potential therapeutic advantage of CB1 biased signaling in different pathological states. Agonist and antagonist bound structures of CB1 and proposed mechanisms of action of biased allosteric modulators are used to discuss a putative molecular mechanism for CB1 receptor activation and biased signaling. Current studies suggest that allosteric binding sites on CB1 can be explored to yield biased ligands that favor or hinder conformational changes important for biased signaling.

scholarly journals Biased Coupling to β-Arrestin of Two Common Variants of the CB2 Cannabinoid Receptor

2021 ◽  
Vol 12 ◽  
Author(s):  
Gábor Turu ◽  
Eszter Soltész-Katona ◽  
András Dávid Tóth ◽  
Cintia Juhász ◽  
Miklós Cserző ◽  
...  
Keyword(s):  
G Protein ◽  
Intracellular Trafficking ◽  
Cannabinoid Receptor ◽  
Therapeutic Potential ◽  
Receptor Activation ◽  
Missense Mutations ◽  
Common Variants ◽  
Biased Signaling ◽  
The Central Nervous System ◽  
G Protein Coupled

β-arrestins are partners of the G protein-coupled receptors (GPCRs), regulating their intracellular trafficking and signaling. Development of biased GPCR agonists, selectively targeting either G protein or β-arrestin pathways, are in the focus of interest due to their therapeutic potential in different pathological conditions. The CB2 cannabinoid receptor (CB2R) is a GPCR involved in various functions in the periphery and the central nervous system. Two common occurring variants of CB2R, harboring Q63R or L133I missense mutations, have been implicated in the development of a diverse set of disorders. To evaluate the effect of these mutations, we characterized the binding profile of these mutant CB2 receptors to G proteins and β-arrestin2. Although their ability to inhibit cAMP signaling was similar, the Q63R mutant had increased, whereas the L133I mutant receptor had decreased β-arrestin2 binding. In line with these observations, the variants also had altered intracellular trafficking. Our results show that two common variants of the CB2 receptor have biased signaling properties, which may contribute to the pathogenesis of the associated disorders and may offer CB2R as a target for further development of biased receptor activation strategies.

scholarly journals Dissecting the allosteric networks governing agonist efficacy and potency in G protein-coupled receptors

2021 ◽  
Author(s):  
Franziska Marie Heydenreich ◽  
Maria Marti-Solano ◽  
Manbir Sandhu ◽  
Brian K Kobilka ◽  
Michel Bouvier ◽  
...  
Keyword(s):  
G Protein ◽  
Conformational Changes ◽  
Structural Changes ◽  
Receptor Activation ◽  
Residue Level ◽  
G Protein Coupled Receptors ◽  
Maximal Response ◽  
Pharmacological Properties ◽  
Receptor Ligand ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs) translate binding of extracellular ligands into intracellular responses through conformational changes. Ligand properties are described by the maximum response (efficacy) and the agonist concentration at half-maximal response (potency). Integrating structural changes with pharmacological properties remains challenging and has not yet been performed at the resolution of individual amino acids. We use epinephrine and β2-adrenergic receptor as a model to integrate residue-level pharmacology data with intramolecular residue contact data describing receptor activation. This unveils the allosteric networks driving ligand efficacy and potency. We provide detailed insights into how structural rearrangements are linked to fundamental pharmacological properties at single-residue level in a receptor-ligand system. Our approach can be used to determine such pharmacological networks for any receptor-ligand complex.

scholarly journals The Role of ICL1 and H8 in Class B1 GPCRs; Implications for Receptor Activlation

2022 ◽  
Vol 12 ◽  
Author(s):  
Ian Winfield ◽  
Kerry Barkan ◽  
Sarah Routledge ◽  
Nathan J. Robertson ◽  
Matthew Harris ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
G Protein ◽  
Conformational Changes ◽  
Transmembrane Helix ◽  
Receptor Activation ◽  
Cgrp Receptor ◽  
Intracellular Loop ◽  
Glucagon Receptor ◽  
G Protein Coupled

The first intracellular loop (ICL1) of G protein-coupled receptors (GPCRs) has received little attention, although there is evidence that, with the 8th helix (H8), it is involved in early conformational changes following receptor activation as well as contacting the G protein β subunit. In class B1 GPCRs, the distal part of ICL1 contains a conserved R12.48KLRCxR2.46b motif that extends into the base of the second transmembrane helix; this is weakly conserved as a [R/H]12.48KL[R/H] motif in class A GPCRs. In the current study, the role of ICL1 and H8 in signaling through cAMP, iCa2+ and ERK1/2 has been examined in two class B1 GPCRs, using mutagenesis and molecular dynamics. Mutations throughout ICL1 can either enhance or disrupt cAMP production by CGRP at the CGRP receptor. Alanine mutagenesis identified subtle differences with regard elevation of iCa2+, with the distal end of the loop being particularly sensitive. ERK1/2 activation displayed little sensitivity to ICL1 mutation. A broadly similar pattern was observed with the glucagon receptor, although there were differences in significance of individual residues. Extending the study revealed that at the CRF1 receptor, an insertion in ICL1 switched signaling bias between iCa2+ and cAMP. Molecular dynamics suggested that changes in ICL1 altered the conformation of ICL2 and the H8/TM7 junction (ICL4). For H8, alanine mutagenesis showed the importance of E3908.49b for all three signal transduction pathways, for the CGRP receptor, but mutations of other residues largely just altered ERK1/2 activation. Thus, ICL1 may modulate GPCR bias via interactions with ICL2, ICL4 and the Gβ subunit.

scholarly journals Conformational changes involved in G-protein-coupled-receptor activation

2008 ◽  
Vol 29 (12) ◽  
pp. 616-625 ◽  
Author(s):  
Jürgen Wess ◽  
Sung-Jun Han ◽  
Soo-Kyung Kim ◽  
Kenneth A. Jacobson ◽  
Jian Hua Li
Keyword(s):  
G Protein ◽  
Conformational Changes ◽  
Receptor Activation ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled

scholarly journals Crystal structure of rhodopsin bound to arrestin by femtosecond X-ray laser

2014 ◽  
Vol 70 (a1) ◽  
pp. C567-C567
Author(s):  
H. Eric Xu
Keyword(s):  
Crystal Structure ◽  
G Protein ◽  
Conformational Changes ◽  
Molten Globule ◽  
Active Form ◽  
New Paradigm ◽  
X Ray ◽  
Biased Signaling ◽  
G Protein Coupled ◽  
Β Sheet

G protein-coupled receptors (GPCRs) signal primarily through G proteins or arrestins. Arrestin binding to GPCRs blocks G protein interaction and redirects signaling to numerous G protein-independent pathways. One structure of a GPCR bound to a G protein was solved, but the structure of a GPCR-arrestin complex has remained unknown despite its central role in GPCR biology. Here we report the crystal structure of a constitutively active form of human rhodopsin bound to a pre-activated form of the mouse visual arrestin, determined by serial femtosecond X-ray laser crystallography. The structure reveals that arrestin binding induces large and unexpected conformational changes at both the extracellular and intracellular sides of rhodopsin. Arrestin also undergoes dramatic rearrangements from its inactive well-ordered β-sheet structure into a more flexible molten globule-type state, allowing a snake-like movement of the first 77 arrestin residues that shortens its central crest finger loop by seven residues to accommodate the concave surface of rhodopsin. This structure provides a basis for understanding GPCR-mediated arrestin-biased signaling, reveals a new paradigm of signal transduction by a molten globule, and demonstrates the extraordinary power of X-ray lasers for advancing the frontiers of structural biology.

scholarly journals The Molecular Basis of G Protein–Coupled Receptor Activation

2018 ◽  
Vol 87 (1) ◽  
pp. 897-919 ◽  
Author(s):  
William I. Weis ◽  
Brian K. Kobilka
Keyword(s):  
Ligand Binding ◽  
G Protein ◽  
Conformational Changes ◽  
Cellular Responses ◽  
Receptor Activation ◽  
G Protein Coupled Receptors ◽  
Active Conformation ◽  
Allosteric Coupling ◽  
External Stimuli ◽  
G Protein Coupled

G protein–coupled receptors (GPCRs) mediate the majority of cellular responses to external stimuli. Upon activation by a ligand, the receptor binds to a partner heterotrimeric G protein and promotes exchange of GTP for GDP, leading to dissociation of the G protein into α and βγ subunits that mediate downstream signals. GPCRs can also activate distinct signaling pathways through arrestins. Active states of GPCRs form by small rearrangements of the ligand-binding, or orthosteric, site that are amplified into larger conformational changes. Molecular understanding of the allosteric coupling between ligand binding and G protein or arrestin interaction is emerging from structures of several GPCRs crystallized in inactive and active states, spectroscopic data, and computer simulations. The coupling is loose, rather than concerted, and agonist binding does not fully stabilize the receptor in an active conformation. Distinct intermediates whose populations are shifted by ligands of different efficacies underlie the complex pharmacology of GPCRs.

scholarly journals Emerging roles of adhesion G protein-coupled receptors

2021 ◽  
Author(s):  
Matthew Rosa ◽  
Timothy Noel ◽  
Matthew Harris ◽  
Graham Ladds
Keyword(s):  
G Protein ◽  
Conformational Changes ◽  
Current Knowledge ◽  
Receptor Activation ◽  
G Protein Coupled Receptors ◽  
Extracellular Region ◽  
Extracellular Matrix Components ◽  
Ligand Interactions ◽  
Tethered Ligand ◽  
G Protein Coupled

Adhesion G protein-coupled receptors (aGPCRs) form a sub-group within the GPCR superfamily. Their distinctive structure contains an abnormally large N-terminal, extracellular region with a GPCR autoproteolysis-inducing (GAIN) domain. In most aGPCRs, the GAIN domain constitutively cleaves the receptor into two fragments. This process is often required for aGPCR signalling. Over the last two decades, much research has focussed on aGPCR-ligand interactions, in an attempt to deorphanize the family. Most ligands have been found to bind to regions N-terminal to the GAIN domain. These receptors may bind a variety of ligands, ranging across membrane-bound proteins and extracellular matrix components. Recent advancements have revealed a conserved method of aGPCR activation involving a tethered ligand within the GAIN domain. Evidence for this comes from increased activity in receptor mutants exposing the tethered ligand. As a result, G protein-coupling partners of aGPCRs have been more extensively characterised, making use of their tethered ligand to create constitutively active mutants. This has led to demonstrations of aGPCR function in, for example, neurodevelopment and tumour growth. However, questions remain around the ligands that may bind many aGPCRs, how this binding is translated into changes in the GAIN domain, and the exact mechanism of aGPCR activation following GAIN domain conformational changes. This review aims to examine the current knowledge around aGPCR activation, including ligand binding sites, the mechanism of GAIN domain-mediated receptor activation and how aGPCR transmembrane domains may relate to activation. Other aspects of aGPCR signalling will be touched upon, such as downstream effectors and physiological roles.

scholarly journals Autoantibody and hormone activation of the thyrotropin G protein-coupled receptor

2022 ◽  
Author(s):  
Bryan Faust ◽  
Isha Singh ◽  
Kaihua Zhang ◽  
Nicholas Hoppe ◽  
Antonio F.M. Pinto ◽  
...  
Keyword(s):  
Thyroid Hormones ◽  
G Protein ◽  
Conformational Changes ◽  
Hormone Receptors ◽  
Transmembrane Domain ◽  
Extracellular Domain ◽  
Receptor Activation ◽  
Glycoprotein Hormone ◽  
Membrane Bilayer ◽  
G Protein Coupled

Thyroid hormones are vital to growth and metabolism. Thyroid hormone synthesis is controlled by thyrotropin (TSH), which acts at the thyrotropin receptor (TSHR). Autoantibodies that activate the TSHR pathologically increase thyroid hormones in Graves' disease. How autoantibodies mimic TSH function remains unclear. We determined cryogenic-electron microscopy structures of active and inactive TSHR. In inactive TSHR, the extracellular domain lies close to the membrane bilayer. TSH selects an upright conformation of the extracellular domain due to steric clashes between a conserved hormone glycan and the membrane bilayer. An activating autoantibody selects a similar upright conformation of the extracellular domain. Conformational changes in the extracellular domain are transduced to the seven transmembrane domain via a conserved hinge domain, a tethered peptide agonist, and a phospholipid that binds within the seven transmembrane domain. Rotation of the TSHR ECD relative to the membrane bilayer is sufficient for receptor activation, revealing a shared mechanism for other glycoprotein hormone receptors that may also extend to G protein-coupled receptors with large extracellular domains.

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