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

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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G Protein-Coupled Receptors in Taste Physiology and Pharmacology

Frontiers in Pharmacology ◽

10.3389/fphar.2020.587664 ◽

2020 ◽

Vol 11 ◽

Author(s):

Raise Ahmad ◽

Julie E. Dalziel

Keyword(s):

Binding Site ◽

G Protein ◽

Molecular Mechanisms ◽

Taste Receptor ◽

Receptor Activation ◽

G Protein Coupled Receptors ◽

Type I ◽

Taste Receptors ◽

Agonist Binding ◽

G Protein Coupled

Heterotrimeric G protein-coupled receptors (GPCRs) comprise the largest receptor family in mammals and are responsible for the regulation of most physiological functions. Besides mediating the sensory modalities of olfaction and vision, GPCRs also transduce signals for three basic taste qualities of sweet, umami (savory taste), and bitter, as well as the flavor sensation kokumi. Taste GPCRs reside in specialised taste receptor cells (TRCs) within taste buds. Type I taste GPCRs (TAS1R) form heterodimeric complexes that function as sweet (TAS1R2/TAS1R3) or umami (TAS1R1/TAS1R3) taste receptors, whereas Type II are monomeric bitter taste receptors or kokumi/calcium-sensing receptors. Sweet, umami and kokumi receptors share structural similarities in containing multiple agonist binding sites with pronounced selectivity while most bitter receptors contain a single binding site that is broadly tuned to a diverse array of bitter ligands in a non-selective manner. Tastant binding to the receptor activates downstream secondary messenger pathways leading to depolarization and increased intracellular calcium in TRCs, that in turn innervate the gustatory cortex in the brain. Despite recent advances in our understanding of the relationship between agonist binding and the conformational changes required for receptor activation, several major challenges and questions remain in taste GPCR biology that are discussed in the present review. In recent years, intensive integrative approaches combining heterologous expression, mutagenesis and homology modeling have together provided insight regarding agonist binding site locations and molecular mechanisms of orthosteric and allosteric modulation. In addition, studies based on transgenic mice, utilizing either global or conditional knock out strategies have provided insights to taste receptor signal transduction mechanisms and their roles in physiology. However, the need for more functional studies in a physiological context is apparent and would be enhanced by a crystallized structure of taste receptors for a more complete picture of their pharmacological mechanisms.

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G‐protein‐coupled receptors: molecular mechanisms involved in receptor activation and selectivity of G‐protein recognition

The FASEB Journal ◽

10.1096/fasebj.11.5.9141501 ◽

1997 ◽

Vol 11 (5) ◽

pp. 346-354 ◽

Cited By ~ 405

Author(s):

Jürgen Wess

Keyword(s):

G Protein ◽

Molecular Mechanisms ◽

Receptor Activation ◽

G Protein Coupled Receptors ◽

Protein Recognition ◽

G Protein Coupled

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

Cells ◽

10.3390/cells10051228 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1228

Author(s):

Tomasz Boczek ◽

Joanna Mackiewicz ◽

Marta Sobolczyk ◽

Julia Wawrzyniak ◽

Malwina Lisek ◽

...

Keyword(s):

G Protein ◽

Psychiatric Illness ◽

Antipsychotic Drugs ◽

Molecular Mechanisms ◽

Critical Role ◽

G Protein Coupled Receptors ◽

Disease Development ◽

Complex Picture ◽

G Protein Coupled

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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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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Identification of select G-protein coupled receptors as regulators of the ER-mitochondria contacts by drug screening

10.1101/2020.05.11.088815 ◽

2020 ◽

Author(s):

Youngshin Lim ◽

Il-Taeg Cho ◽

Helmut G. Rennke ◽

Ginam Cho

Keyword(s):

G Protein ◽

Actin Polymerization ◽

Metabolic Diseases ◽

Receptor Activation ◽

G Protein Coupled Receptors ◽

Cellular Functions ◽

Regulatory Pathways ◽

Physiological Demands ◽

G Protein Coupled

AbstractEndoplasmic reticulum-mitochondrial (ER-Mito) contacts are crucial for many cellular functions. Their dysregulation has been implicated in various disorders including neurodegenerative, cardiovascular and metabolic diseases, and cancer. However, little is known about the regulatory pathways of ER-Mito contacts. To uncover such pathways, we screened a drug library using a split-Renilla luciferase (split-Rluc) reassembly assay in HEK293T cells. We identified multiple agonists of G-protein coupled receptors (GPCRs), beta-adrenergic receptors (β-ARs) in particular. Using multiple independent assays, we validated that these drugs enhance the physical and functional interactions between ER and mitochondria. Our data provide evidence that GPCR signal modulates ER-Mito coupling through activating EPAC (exchange protein directly activated by cAMP) and increasing cytoplasmic Ca2+ levels, and that actin polymerization, likely regulated by CDC42 upon receptor activation, is required for this coupling. Together our study identifies GPCR signaling as a regulatory mechanism for ER-Mito contacts, and highlights the role of these contacts in responding to physiological demands or stresses.

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Molecular mechanisms involved in vasoactive intestinal peptide receptor activation and regulation: current knowledge, similarities to and differences from the A family of G-protein-coupled receptors

Biochemical Society Transactions ◽

10.1042/bst0350724 ◽

2007 ◽

Vol 35 (4) ◽

pp. 724-728 ◽

Cited By ~ 28

Author(s):

I. Langer ◽

P. Robberecht

Keyword(s):

Vasoactive Intestinal Peptide ◽

G Protein ◽

Molecular Mechanisms ◽

Current Knowledge ◽

Transmembrane Helix ◽

Receptor Activation ◽

G Protein Coupled Receptors ◽

Peptide Receptor ◽

Vasoactive Intestinal Peptide Receptor ◽

G Protein Coupled

An actual paradigm for activation and regulation of the GPCR (G-protein-coupled receptors)/seven-transmembrane helix family of receptors essentially emerges from extensive studies of the largest family of receptors, the GPCR-A/rhodopsin family. The mechanisms regulating the GPCR-B family signal transduction are less precisely understood due in part to the lack of the conserved signatures of the GPCR-A family (E/DRY, NPXXY) and in part to the absence of a reliable receptor modelling, although some studies suggest that both families share similar features. Here, we try to highlight the current knowledge of the activation and the regulation of the VIP (vasoactive intestinal peptide) receptors, namely VPAC (VIP/pituitary adenylate cyclase-activating peptide receptor) 1 and 2. This includes search for amino acids involved in the stabilization of the receptor active conformation and in coupling to G-proteins, signalling pathways activated in response to VIP, agonist-dependent receptor down-regulation, phosphorylation and internalization as well as pharmacological consequences of receptor hetero-dimerization.

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Molecular mechanisms of metabotropic GABAB receptor function

Science Advances ◽

10.1126/sciadv.abg3362 ◽

2021 ◽

Vol 7 (22) ◽

pp. eabg3362

Author(s):

Hamidreza Shaye ◽

Benjamin Stauch ◽

Cornelius Gati ◽

Vadim Cherezov

Keyword(s):

G Protein ◽

Molecular Mechanisms ◽

Gabab Receptor ◽

Neurological Diseases ◽

Activation Mechanism ◽

Allosteric Modulators ◽

Inhibitory Neurotransmitter ◽

Therapeutic Drugs ◽

G Protein Coupled ◽

The Brain

Metabotropic γ-aminobutyric acid G protein–coupled receptors (GABAB) represent one of the two main types of inhibitory neurotransmitter receptors in the brain. These receptors act both pre- and postsynaptically by modulating the transmission of neuronal signals and are involved in a range of neurological diseases, from alcohol addiction to epilepsy. A series of recent cryo-EM studies revealed critical details of the activation mechanism of GABAB. Structures are now available for the receptor bound to ligands with different modes of action, including antagonists, agonists, and positive allosteric modulators, and captured in different conformational states from the inactive apo to the fully active state bound to a G protein. These discoveries provide comprehensive insights into the activation of the GABAB receptor, which not only broaden our understanding of its structure, pharmacology, and physiological effects but also will ultimately facilitate the discovery of new therapeutic drugs and neuromodulators.

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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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