scholarly journals G-Protein-Coupled Receptors in CNS: A Potential Therapeutic Target for Intervention in Neurodegenerative Disorders and Associated Cognitive Deficits

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 506 ◽  
Author(s):  
Shofiul Azam ◽  
Md. Ezazul Haque ◽  
Md. Jakaria ◽  
Song-Hee Jo ◽  
In-Su Kim ◽  
...  
Keyword(s):  
G Protein ◽  
Cognitive Deficits ◽  
Therapeutic Target ◽  
Neurological Disorders ◽  
Symptomatic Relief ◽  
Underlying Disease ◽  
G Protein Coupled Receptors ◽  
Potential Therapeutic Target ◽  
G Protein Coupled ◽  
Insight Into

Neurodegenerative diseases are a large group of neurological disorders with diverse etiological and pathological phenomena. However, current therapeutics rely mostly on symptomatic relief while failing to target the underlying disease pathobiology. G-protein-coupled receptors (GPCRs) are one of the most frequently targeted receptors for developing novel therapeutics for central nervous system (CNS) disorders. Many currently available antipsychotic therapeutics also act as either antagonists or agonists of different GPCRs. Therefore, GPCR-based drug development is spreading widely to regulate neurodegeneration and associated cognitive deficits through the modulation of canonical and noncanonical signals. Here, GPCRs’ role in the pathophysiology of different neurodegenerative disease progressions and cognitive deficits has been highlighted, and an emphasis has been placed on the current pharmacological developments with GPCRs to provide an insight into a potential therapeutic target in the treatment of neurodegeneration.

scholarly journals Heteromerization of G Protein-Coupled Receptors: Relevance to Neurological Disorders and Neurotherapeutics

2010 ◽  
Vol 9 (5) ◽  
pp. 636-650 ◽  
Author(s):  
Laura Albizu ◽  
Jose L. Moreno ◽  
Javier Gonzalez-Maeso ◽  
Stuart C. Sealfon
Keyword(s):  
G Protein ◽  
Neurological Disorders ◽  
G Protein Coupled Receptors ◽  
G Protein Coupled

Signaling and regulation of G-protein coupled receptors encoded by cytomegaloviruses

2004 ◽  
Vol 82 (6) ◽  
pp. 636-642 ◽  
Author(s):  
Melissa P. M Stropes ◽  
William E Miller
Keyword(s):  
Immune Response ◽  
Host Cell ◽  
G Protein ◽  
Host Immune Response ◽  
G Protein Coupled Receptors ◽  
Molecular Regulation ◽  
Virally Encoded ◽  
Species Specific ◽  
G Protein Coupled ◽  
Insight Into

Cytomegaloviruses (CMVs) are species-specific β-herpesviruses whose replicative success is largely due to establishment of novel mechanisms for altering the host immune response. CMV encodes 3 families of putative G-protein coupled receptors (GPCRs) likely pirated from the host cell. While the functions of these virally encoded GPCRs remain unclear, the receptors possess potent signaling abilities. Understanding the molecular regulation of these GPCRs will provide important insight into CMV pathogenesis.Key words: GPCRs, HCMV, GRKs, β-arrestin, US28.

scholarly journals Cardiac hyporesponsiveness in severe sepsis is associated with nitric oxide-dependent activation of G protein receptor kinase

2017 ◽  
Vol 313 (1) ◽  
pp. H149-H163 ◽  
Author(s):  
Daniela Dal-Secco ◽  
Silvia DalBó ◽  
Natalia E. S. Lautherbach ◽  
Fábio N. Gava ◽  
Mara R. N. Celes ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
G Protein ◽  
Cardiac Dysfunction ◽  
Therapeutic Target ◽  
Adrenergic Receptor ◽  
Receptor Density ◽  
Receptor Kinase ◽  
G Protein Coupled Receptor ◽  
Potential Therapeutic Target ◽  
G Protein Coupled

G protein-coupled receptor kinase isoform 2 (GRK2) has a critical role in physiological and pharmacological responses to endogenous and exogenous substances. Sepsis causes an important cardiovascular dysfunction in which nitric oxide (NO) has a relevant role. The present study aimed to assess the putative effect of inducible NO synthase (NOS2)-derived NO on the activity of GRK2 in the context of septic cardiac dysfunction. C57BL/6 mice were submitted to severe septic injury by cecal ligation and puncture (CLP). Heart function was assessed by isolated and perfused heart, echocardiography, and β-adrenergic receptor binding. GRK2 was determined by immunofluorescence and Western blot analysis in the heart and isolated cardiac myocytes. Sepsis increased NOS2 expression in the heart, increased plasma nitrite + nitrate levels, and reduced isoproterenol-induced isolated ventricle contraction, whole heart tension development, and β-adrenergic receptor density. Treatment with 1400W or with GRK2 inhibitor prevented CLP-induced cardiac hyporesponsiveness 12 and 24 h after CLP. Increased labeling of total and phosphorylated GRK2 was detected in hearts after CLP. With treatment of 1400W or in hearts taken from septic NOS2 knockout mice, the activation of GRK2 was reduced. 1400W or GRK2 inhibitor reduced mortality, improved echocardiographic cardiac parameters, and prevented organ damage. Therefore, during sepsis, NOS2-derived NO increases GRK2, which leads to a reduction in β-adrenergic receptor density, contributing to the heart dysfunction. Isolated cardiac myocyte data indicate that NO acts through the soluble guanylyl cyclase/cGMP/PKG pathway. GRK2 inhibition may be a potential therapeutic target in sepsis-induced cardiac dysfunction. NEW & NOTEWORTHY The main novelty presented here is to show that septic shock induces cardiac hyporesponsiveness to isoproterenol by a mechanism dependent on nitric oxide and mediated by G protein-coupled receptor kinase isoform 2. Therefore, G protein-coupled receptor kinase isoform 2 inhibition may be a potential therapeutic target in sepsis-induced cardiac dysfunction.

scholarly journals An allosteric role for receptor activity-modifying proteins in defining GPCR pharmacology

2016 ◽  
Vol 2 (1) ◽  
Author(s):  
Joseph J Gingell ◽  
John Simms ◽  
James Barwell ◽  
David R Poyner ◽  
Harriet A Watkins ◽  
...  
Keyword(s):  
G Protein ◽  
Protein Interaction ◽  
G Protein Coupled Receptors ◽  
Receptor Activity ◽  
Calcitonin Receptor ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Receptor Activity Modifying Proteins ◽  
G Protein Coupled ◽  
Insight Into

Abstract G protein-coupled receptors are allosteric proteins that control transmission of external signals to regulate cellular response. Although agonist binding promotes canonical G protein signalling transmitted through conformational changes, G protein-coupled receptors also interact with other proteins. These include other G protein-coupled receptors, other receptors and channels, regulatory proteins and receptor-modifying proteins, notably receptor activity-modifying proteins (RAMPs). RAMPs have at least 11 G protein-coupled receptor partners, including many class B G protein-coupled receptors. Prototypic is the calcitonin receptor, with altered ligand specificity when co-expressed with RAMPs. To gain molecular insight into the consequences of this protein–protein interaction, we combined molecular modelling with mutagenesis of the calcitonin receptor extracellular domain, assessed in ligand binding and functional assays. Although some calcitonin receptor residues are universally important for peptide interactions (calcitonin, amylin and calcitonin gene-related peptide) in calcitonin receptor alone or with receptor activity-modifying protein, others have RAMP-dependent effects, whereby mutations decreased amylin/calcitonin gene-related peptide potency substantially only when RAMP was present. Remarkably, the key residues were completely conserved between calcitonin receptor and AMY receptors, and between subtypes of AMY receptor that have different ligand preferences. Mutations at the interface between calcitonin receptor and RAMP affected ligand pharmacology in a RAMP-dependent manner, suggesting that RAMP may allosterically influence the calcitonin receptor conformation. Supporting this, molecular dynamics simulations suggested that the calcitonin receptor extracellular N-terminal domain is more flexible in the presence of receptor activity-modifying protein 1. Thus, RAMPs may act in an allosteric manner to generate a spectrum of unique calcitonin receptor conformational states, explaining the pharmacological preferences of calcitonin receptor-RAMP complexes. This provides novel insight into our understanding of G protein-coupled receptor-protein interaction that is likely broadly applicable for this receptor class.

Consequences of lipid raft association on G-protein-coupled receptor function.

2005 ◽  
Vol 72 ◽  
pp. 151-164 ◽  
Author(s):  
Anja Becher ◽  
R. A. Jeffrey McIlhinney
Keyword(s):  
G Protein ◽  
Lipid Rafts ◽  
Lipid Raft ◽  
Neurological Disorders ◽  
G Protein Coupled Receptors ◽  
Membrane Microdomains ◽  
Pharmaceutical Drug ◽  
Cellular Processes ◽  
G Protein Coupled ◽  
Specific Membrane

GPCRs (G-protein-coupled receptors) play key roles in many cellular processes, and malfunction may lead to a range of pathologies, including psychiatric and neurological disorders. It is therefore not surprising that this group of receptors supplies a majority of the targets for pharmaceutical drug development. Despite their importance, the mechanisms that regulate their function and signalling still remain only partially understood. Recently, it has become evident that a subset of GPCRs is not homogeneously distributed in the plasma membrane, but localizes instead to specific membrane microdomains known as lipid rafts. Lipid rafts are characterized by their enrichment in cholesterol and sphingolipids, and have been suggested to serve as platforms for a range of cellular signalling complexes. In the present review, we will be discussing the effects of the lipid raft environment on trafficking, signalling and internalization of raft-associated GPCRs.

scholarly journals Computational Insight into the Ligand-Induced Conformational Specificity of G-Protein Coupled Receptors

2010 ◽  
Vol 98 (3) ◽  
pp. 290a
Author(s):  
Davide Provasi ◽  
Juan Carlos Mobarec ◽  
Marta Camacho Artacho ◽  
Marta Filizola
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
G Protein Coupled ◽  
Insight Into
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