The Role of G Protein-Coupled Receptors (GPCRs) and Calcium Signaling in Schizophrenia. Focus on GPCRs Activated by Neurotransmitters and Chemokines

Schizophrenia is a common debilitating disease characterized by continuous or relapsing episodes of psychosis. Although the molecular mechanisms underlying this psychiatric illness remain incompletely understood, a growing body of clinical, pharmacological, and genetic evidence suggests that G protein-coupled receptors (GPCRs) play a critical role in disease development, progression, and treatment. This pivotal role is further highlighted by the fact that GPCRs are the most common targets for antipsychotic drugs. The GPCRs activation evokes slow synaptic transmission through several downstream pathways, many of them engaging intracellular Ca2+ mobilization. Dysfunctions of the neurotransmitter systems involving the action of GPCRs in the frontal and limbic-related regions are likely to underly the complex picture that includes the whole spectrum of positive and negative schizophrenia symptoms. Therefore, the progress in our understanding of GPCRs function in the control of brain cognitive functions is expected to open new avenues for selective drug development. In this paper, we review and synthesize the recent data regarding the contribution of neurotransmitter-GPCRs signaling to schizophrenia symptomology.

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Molecular mechanisms of GABAB receptor activation: new insights from the mechanism of action of CGP7930, a positive allosteric modulator

Biochemical Society Transactions ◽

10.1042/bst0320871 ◽

2004 ◽

Vol 32 (5) ◽

pp. 871-872 ◽

Cited By ~ 15

Author(s):

V. Binet ◽

C. Goudet ◽

C. Brajon ◽

L. Le Corre ◽

F. Acher ◽

...

Keyword(s):

G Protein ◽

Mechanism Of Action ◽

Molecular Mechanisms ◽

Gabab Receptor ◽

Receptor Activation ◽

G Protein Coupled Receptors ◽

Class Iii ◽

G Protein Coupled ◽

New Strategies

The GABAB (γ-aminobutyric acid-B) receptor is composed of two subunits, GABAB1 and GABAB2. Both subunits share structural homology with other class-III G-protein-coupled receptors. They contain two main domains, a heptahelical domain typical of all G-protein-coupled receptors and a large ECD (extracellular domain). It has not been demonstrated whether the association of these two subunits is always required for function. However, GABAB2 plays a major role in coupling with G-proteins, and GABAB1 has been shown to bind GABA. To date, only ligands interacting with GABAB1-ECD have been identified. In the present study, we explored the mechanism of action of CGP7930, a compound described as a positive allosteric regulator of the GABAB receptor. We have shown that it can weakly activate the wild-type GABAB receptor, but also the GABAB2 expressed alone, thus being the first described agonist of GABAB2. CGP7930 retains its weak agonist activity on a GABAB2 subunit deleted of its ECD. Thus the heptahelical domain of GABAB2 behaves similar to a rhodopsin-like receptor. These results open new strategies for studying the mechanism of activation of GABAB receptor and examine any possible role of GABAB2.

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Sa1336 Molecular Mechanisms Underlying the Critical Role of the G Protein-Coupled Receptor 30 (GPR30), a Novel Estrogen Receptor, in the Formation of Lithogenic Bile Through a Non-Transcriptional Regulatory Mode in 17β-Estradiol (E2)-Treated Mice

Gastroenterology ◽

10.1016/s0016-5085(15)30976-8 ◽

2015 ◽

Vol 148 (4) ◽

pp. S-295 ◽

Cited By ~ 1

Author(s):

Ornella de Bari ◽

Helen H. Wang ◽

Piero Portincasa ◽

Min Liu ◽

David Q. Wang

Keyword(s):

Estrogen Receptor ◽

G Protein ◽

Molecular Mechanisms ◽

Critical Role ◽

G Protein Coupled Receptor ◽

Regulatory Mode ◽

Transcriptional Regulatory ◽

17Β Estradiol ◽

G Protein Coupled

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G protein-coupled receptors that influence lifespan of human and animal models

Biogerontology ◽

10.1007/s10522-021-09945-8 ◽

2021 ◽

Author(s):

Francisco Alejandro Lagunas-Rangel

Keyword(s):

G Protein ◽

Insulin Signaling ◽

Molecular Mechanisms ◽

Good Health ◽

G Protein Coupled Receptors ◽

Multiple Strategies ◽

G Protein Coupled ◽

Harmful Effects ◽

Oxidative Homeostasis

AbstractHumanity has always sought to live longer and for this, multiple strategies have been tried with varying results. In this sense, G protein-coupled receptors (GPCRs) may be a good option to try to prolong our life while maintaining good health since they have a substantial participation in a wide variety of processes of human pathophysiology and are one of the main therapeutic targets. In this way, we present the analysis of a series of GPCRs whose activity has been shown to affect the lifespan of animal and human models, and in which we put a special interest in describing the molecular mechanisms involved. Our compilation of data revealed that the mechanisms most involved in the role of GPCRs in lifespan are those that mimic dietary restriction, those related to insulin signaling and the AMPK and TOR pathways, and those that alter oxidative homeostasis and severe and/or chronic inflammation. We also discuss the possibility of using agonist or antagonist drugs, depending on the beneficial or harmful effects of each GPCR, in order to prolong people's lifespan and healthspan.

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The role of water molecules in phototransduction of retinal proteins and G protein-coupled receptors

Faraday Discussions ◽

10.1039/c7fd00207f ◽

2018 ◽

Vol 207 ◽

pp. 27-37 ◽

Cited By ~ 2

Author(s):

Elena Lesca ◽

Valérie Panneels ◽

Gebhard F. X. Schertler

Keyword(s):

G Protein ◽

Critical Role ◽

G Protein Coupled Receptors ◽

Water Molecules ◽

Important Class ◽

Retinal Proteins ◽

G Protein Coupled

Water molecules play a critical role during activation of GPCRs, one of the most important class of signalling proteins.

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G-protein-coupled receptors signalling at the cell nucleus: an emerging paradigmThis paper is one of a selection of papers published in this Special Issue, entitled The Nucleus: A Cell Within A Cell.

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y05-127 ◽

2006 ◽

Vol 84 (3-4) ◽

pp. 287-297 ◽

Cited By ~ 124

Author(s):

Fernand Gobeil ◽

Audrey Fortier ◽

Tang Zhu ◽

Michela Bossolasco ◽

Martin Leduc ◽

...

Keyword(s):

G Protein ◽

Cell Nucleus ◽

Intracellular Signaling ◽

Molecular Mechanisms ◽

Nuclear Translocation ◽

Cell Metabolism ◽

Hormone Secretion ◽

G Protein Coupled Receptors ◽

A Cell ◽

G Protein Coupled

G-protein-coupled receptors (GPCRs) comprise a wide family of monomeric heptahelical glycoproteins that recognize a broad array of extracellular mediators including cationic amines, lipids, peptides, proteins, and sensory agents. Thus far, much attention has been given towards the comprehension of intracellular signaling mechanisms activated by cell membrane GPCRs, which convert extracellular hormonal stimuli into acute, non-genomic (e.g., hormone secretion, muscle contraction, and cell metabolism) and delayed, genomic biological responses (e.g., cell division, proliferation, and apoptosis). However, with respect to the latter response, there is compelling evidence for a novel intracrine mode of genomic regulation by GPCRs that implies either the endocytosis and nuclear translocation of peripheral-liganded GPCR and (or) the activation of nuclearly located GPCR by endogenously produced, nonsecreted ligands. A noteworthy example of the last scenario is given by heptahelical receptors that are activated by bioactive lipoids (e.g., PGE2 and PAF), many of which may be formed from bilayer membranes including those of the nucleus. The experimental evidence for the nuclear localization and signalling of GPCRs will be reviewed. We will also discuss possible molecular mechanisms responsible for the atypical compartmentalization of GPCRs at the cell nucleus, along with their role in gene expression.

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Ionotropic and Metabotropic Proton-Sensing Receptors Involved in Airway Inflammation in Allergic Asthma

Mediators of Inflammation ◽

10.1155/2014/712962 ◽

2014 ◽

Vol 2014 ◽

pp. 1-8 ◽

Cited By ~ 23

Author(s):

Haruka Aoki ◽

Chihiro Mogi ◽

Fumikazu Okajima

Keyword(s):

Airway Inflammation ◽

Allergic Asthma ◽

G Protein ◽

Molecular Mechanisms ◽

G Protein Coupled Receptors ◽

Airway Smooth Muscle Cells ◽

Transient Receptor Potential Vanilloid ◽

Acidic Ph ◽

Airway Responses ◽

G Protein Coupled

An acidic microenvironment has been shown to evoke a variety of airway responses, including cough, bronchoconstriction, airway hyperresponsiveness (AHR), infiltration of inflammatory cells in the lung, and stimulation of mucus hyperproduction. Except for the participation of transient receptor potential vanilloid-1 (TRPV1) and acid-sensing ion channels (ASICs) in severe acidic pH (of less than 6.0)-induced cough and bronchoconstriction through sensory neurons, the molecular mechanisms underlying extracellular acidic pH-induced actions in the airways have not been fully understood. Recent studies have revealed that ovarian cancer G protein-coupled receptor 1 (OGR1)-family G protein-coupled receptors, which sense pH of more than 6.0, are expressed in structural cells, such as airway smooth muscle cells and epithelial cells, and in inflammatory and immune cells, such as eosinophils and dendritic cells. They function in a variety of airway responses related to the pathophysiology of inflammatory diseases, including allergic asthma. In the present review, we discuss the roles of ionotropic TRPV1 and ASICs and metabotropic OGR1-family G protein-coupled receptors in the airway inflammation and AHR in asthma and respiratory diseases.

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The Role of G Protein-Coupled Receptors in the Right Ventricle in Pulmonary Hypertension

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2018.00179 ◽

2018 ◽

Vol 5 ◽

Cited By ~ 2

Author(s):

Gayathri Viswanathan ◽

Argen Mamazhakypov ◽

Ralph T. Schermuly ◽

Sudarshan Rajagopal

Keyword(s):

Pulmonary Hypertension ◽

Right Ventricle ◽

G Protein ◽

G Protein Coupled Receptors ◽

The Right ◽

G Protein Coupled

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Misfolded G Protein-Coupled Receptors and Endocrine Disease. Molecular Mechanisms and Therapeutic Prospects

International Journal of Molecular Sciences ◽

10.3390/ijms222212329 ◽

2021 ◽

Vol 22 (22) ◽

pp. 12329

Author(s):

Alfredo Ulloa-Aguirre ◽

Teresa Zariñán ◽

Eduardo Jardón-Valadez

Keyword(s):

Plasma Membrane ◽

G Protein ◽

Intracellular Signaling ◽

Molecular Mechanisms ◽

G Protein Coupled Receptors ◽

Membrane Receptors ◽

Therapeutic Interventions ◽

Endocrine Function ◽

Receptor Protein ◽

G Protein Coupled

Misfolding of G protein-coupled receptors (GPCRs) caused by mutations frequently leads to disease due to intracellular trapping of the conformationally abnormal receptor. Several endocrine diseases due to inactivating mutations in GPCRs have been described, including X-linked nephrogenic diabetes insipidus, thyroid disorders, familial hypocalciuric hypercalcemia, obesity, familial glucocorticoid deficiency [melanocortin-2 receptor, MC2R (also known as adrenocorticotropin receptor, ACTHR), and reproductive disorders. In these mutant receptors, misfolding leads to endoplasmic reticulum retention, increased intracellular degradation, and deficient trafficking of the abnormal receptor to the cell surface plasma membrane, causing inability of the receptor to interact with agonists and trigger intracellular signaling. In this review, we discuss the mechanisms whereby mutations in GPCRs involved in endocrine function in humans lead to misfolding, decreased plasma membrane expression of the receptor protein, and loss-of-function diseases, and also describe several experimental approaches employed to rescue trafficking and function of the misfolded receptors. Special attention is given to misfolded GPCRs that regulate reproductive function, given the key role played by these particular membrane receptors in sexual development and fertility, and recent reports on promising therapeutic interventions targeting trafficking of these defective proteins to rescue completely or partially their normal function.

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