Deciphering the specific role of Gαi/o isoforms: functional selective oxytocin ligands and somatostatin SST5 receptor mutants

2013 ◽  
Vol 41 (1) ◽  
pp. 166-171 ◽  
Author(s):  
Marta Busnelli ◽  
Erika Peverelli ◽  
Giovanna Mantovani ◽  
Anna Spada ◽  
Bice Chini
Keyword(s):  
Somatostatin Receptor ◽  
Receptor Activation ◽  
G Protein Coupled Receptors ◽  
Receptor Coupling ◽  
Biological Responses ◽  
Selective Ligands ◽  
Specific Effector ◽  
G Protein Coupled

Receptor coupling to different G-proteins and β-arrestins has been described for a number of GPCRs (G-protein-coupled receptors), suggesting a multi-state model of receptor activation in which each receptor can assume a number of different active conformations, each capable of promoting the coupling to a specific effector. Consistently, functional-selective ligands and biased agonists have been described to be able to induce and/or stabilize only a subset of specific active conformations. Furthermore, GPCR mutants deficient in selective coupling have been reported. Functional selective ligands and receptor mutants thus constitute unique tools to dissect the specific roles of different effectors, in particular among the Gi/o family. In the present mini-review, we focus on (i) the identification of functional selective OXT (oxytocin)-derived peptides capable of activating single Gi/o isoforms, namely Gi1 or Gi3; and (ii) the characterization of an SS (somatostatin) receptor SST5 mutant selectively impaired in its GoA coupling. These analogues and receptor mutants represent unique tools for examining the contribution of Gi/o isoforms in complex biological responses and open the way for the development of drugs with peculiar selectivity profiles.

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

2004 ◽  
Vol 32 (5) ◽  
pp. 871-872 ◽  
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.

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

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.

scholarly journals Histamine, Metabolic Remodelling and Angiogenesis: A Systems Level Approach

Biomolecules ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 415
Author(s):  
Aurelio A. Moya-García ◽  
Almudena Pino-Ángeles ◽  
Francisca Sánchez-Jiménez ◽  
José Luis Urdiales ◽  
Miguel Ángel Medina
Keyword(s):  
Research Field ◽  
G Protein Coupled Receptors ◽  
Signalling Pathways ◽  
Histamine Metabolism ◽  
Current Information ◽  
Physiological Processes ◽  
Cell Growth And Differentiation ◽  
G Protein Coupled

Histamine is a highly pleiotropic biogenic amine involved in key physiological processes including neurotransmission, immune response, nutrition, and cell growth and differentiation. Its effects, sometimes contradictory, are mediated by at least four different G-protein coupled receptors, which expression and signalling pathways are tissue-specific. Histamine metabolism conforms a very complex network that connect many metabolic processes important for homeostasis, including nitrogen and energy metabolism. This review brings together and analyses the current information on the relationships of the “histamine system” with other important metabolic modules in human physiology, aiming to bridge current information gaps. In this regard, the molecular characterization of the role of histamine in the modulation of angiogenesis-mediated processes, such as cancer, makes a promising research field for future biomedical advances.

scholarly journals Receptor-Arrestin Interactions: The GPCR Perspective

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 218
Author(s):  
Mohammad Seyedabadi ◽  
Mehdi Gharghabi ◽  
Eugenia V. Gurevich ◽  
Vsevolod V. Gurevich
Keyword(s):  
G Proteins ◽  
Molecular Mechanisms ◽  
G Protein Coupled Receptors ◽  
Receptor Internalization ◽  
Affinity Binding ◽  
Receptor Coupling ◽  
High Affinity ◽  
Precise Knowledge ◽  
G Protein Coupled

Arrestins are a small family of four proteins in most vertebrates that bind hundreds of different G protein-coupled receptors (GPCRs). Arrestin binding to a GPCR has at least three functions: precluding further receptor coupling to G proteins, facilitating receptor internalization, and initiating distinct arrestin-mediated signaling. The molecular mechanism of arrestin–GPCR interactions has been extensively studied and discussed from the “arrestin perspective”, focusing on the roles of arrestin elements in receptor binding. Here, we discuss this phenomenon from the “receptor perspective”, focusing on the receptor elements involved in arrestin binding and emphasizing existing gaps in our knowledge that need to be filled. It is vitally important to understand the role of receptor elements in arrestin activation and how the interaction of each of these elements with arrestin contributes to the latter’s transition to the high-affinity binding state. A more precise knowledge of the molecular mechanisms of arrestin activation is needed to enable the construction of arrestin mutants with desired functional characteristics.

A green-fluorescent-protein-based assay for the characterization of G-protein-coupled receptors

2004 ◽  
Vol 332 (1) ◽  
pp. 38-45 ◽  
Author(s):  
Thomas Roeder ◽  
Derk Görich ◽  
Dörte Heyden ◽  
Michael Gewecke
Keyword(s):  
Green Fluorescent Protein ◽  
G Protein ◽  
Fluorescent Protein ◽  
G Protein Coupled Receptors ◽  
Green Fluorescent ◽  
G Protein Coupled

scholarly journals Role of Taste Receptors as Sentinels of Innate Immunity in the Upper Airway

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Neil N. Patel ◽  
Alan D. Workman ◽  
Noam A. Cohen
Keyword(s):  
Airway Epithelium ◽  
Taste Receptor ◽  
Upper Airway ◽  
Airway Disease ◽  
G Protein Coupled Receptors ◽  
Innate Immune ◽  
Taste Receptors ◽  
Taste Sensation ◽  
G Protein Coupled

Evidence is emerging that shows taste receptors serve functions outside of taste sensation of the tongue. Taste receptors have been found in tissue across the human body, including the gastrointestinal tract, bladder, brain, and airway. These extraoral taste receptors appear to be important in modulating the innate immune response through detection of pathogens. This review discusses taste receptor signaling, focusing on the G-protein–coupled receptors that detect bitter and sweet compounds in the upper airway epithelium. Emphasis is given to recent studies which link the physiology of sinonasal taste receptors to clinical manifestation of upper airway disease.

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

2018 ◽  
Vol 5 ◽  
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

G-protein-coupled-receptor activation of the smooth muscle calponin gene

2001 ◽  
Vol 357 (2) ◽  
pp. 587-592 ◽  
Author(s):  
Nickolai O. DULIN ◽  
Sergei N. ORLOV ◽  
Chad M. KITCHEN ◽  
Tatyana A. VOYNO-YASENETSKAYA ◽  
Joseph M. MIANO
Keyword(s):  
Smooth Muscle ◽  
Protein Kinase ◽  
G Protein ◽  
Transcriptional Activation ◽  
Fold Increase ◽  
Receptor Activation ◽  
G Protein Coupled Receptors ◽  
Mitogen Activated Protein Kinase ◽  
G Protein Coupled

A hallmark of cultured smooth muscle cells (SMCs) is the rapid down-regulation of several lineage-restricted genes that define their in vivo differentiated phenotype. Identifying factors that maintain an SMC differentiated phenotype has important implications in understanding the molecular underpinnings governing SMC differentiation and their subversion to an altered phenotype in various disease settings. Here, we show that several G-protein coupled receptors [α-thrombin, lysophosphatidic acid and angiotensin II (AII)] increase the expression of smooth muscle calponin (SM-Calp) in rat and human SMC. The increase in SM-Calp protein appears to be selective for G-protein-coupled receptors as epidermal growth factor was without effect. Studies using AII showed a 30-fold increase in SM-Calp protein, which was dose- and time-dependent and mediated by the angiotensin receptor-1 (AT1 receptor). The increase in SM-Calp protein with AII was attributable to transcriptional activation of SM-Calp based on increases in steady-state SM-Calp mRNA, increases in SM-Calp promoter activity and complete abrogation of protein induction with actinomycin D. To examine the potential role of extracellular signal-regulated kinase (Erk1/2), protein kinase B, p38 mitogen-activated protein kinase and protein kinase C in AII-induced SM-Calp, inhibitors to each of the signalling pathways were used. None of these signalling molecules appears to be crucial for AII-induced SM-Calp expression, although Erk1/2 may be partially involved. These results identify SM-Calp as a target of AII-mediated signalling, and suggest that the SMC response to AII may incorporate a novel activity of SM-Calp.

scholarly journals Dopamine and GPCR-mediated modulation of DN1 clock neurons gates the circadian timing of sleep

2021 ◽  
Author(s):  
Matthias Schlichting ◽  
Shlesha Richhariya ◽  
Nicholas Herndon ◽  
Dingbang Ma ◽  
Jason Xin ◽  
...  
Keyword(s):  
G Protein Coupled Receptors ◽  
Sleep Regulation ◽  
Single Cell Sequencing ◽  
Sleep Timing ◽  
Clock Network ◽  
Sleep Centers ◽  
Neuron Synchronization ◽  
G Protein Coupled ◽  
Behavioral Screen

The metronome-like circadian regulation of sleep timing must still adapt to an uncertain environment. Recent studies in Drosophila indicate that neuromodulation not only plays a key role in clock neuron synchronization but also affects interactions between the clock network and brain sleep centers. We show here that the targets of neuromodulators, G-Protein Coupled Receptors (GPCRs), are highly enriched in the fly brain circadian clock network. Single cell sequencing indicates that they are not only differentially expressed but also define clock neuron identity. We generated a comprehensive guide library to mutagenize individual GPCRs in specific neurons and verified the strategy with a targeted sequencing approach. Combined with a behavioral screen, the mutagenesis strategy revealed a novel role of dopamine in sleep regulation by identifying two dopamine receptors and a clock neuron subpopulation that gate the timing of sleep.

scholarly journals Disabling Gβγ SNARE interaction in transgenic mice disrupts GPCR-mediated presynaptic inhibition leading to physiological and behavioral phenotypes

2018 ◽  
Author(s):  
Zack Zurawski ◽  
Analisa D. Thompson Gray ◽  
Lillian J. Brady ◽  
Brian Page ◽  
Emily Church ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Calcium Channels ◽  
G Protein ◽  
Presynaptic Inhibition ◽  
Receptor Activation ◽  
G Protein Coupled Receptors ◽  
Voltage Gated ◽  
Voltage Gated Calcium Channels ◽  
Crucial Component ◽  
G Protein Coupled

ABSTRACTGi/o-coupled G-protein coupled receptors modulate neurotransmission presynaptically through inhibition of exocytosis. Release of Gβγ subunits decreases the activity of voltage-gated calcium channels (VGCC), decreasing excitability. A less understood Gβγ–mediated mechanism downstream of calcium entry is the binding of Gβγ to SNARE complexes. Here, we create a mouse partially deficient in this interaction. SNAP25Δ3 homozygote animals are developmentally normalbut impaired gait and supraspinal nociception. They also have elevated stress-induced hyperthermia and impaired inhibitory postsynaptic responses to α2A-AR, but normal inhibitory postsynaptic responses to Gi/o-coupled GABAB receptor activation. SNAP25Δ3 homozygotes have deficits in inhibition of hippocampal postsynaptic responses to 5 HT1b agonists that affect hippocampal learning. These data suggest that Gi/o-coupled GPCR inhibition of exocytosis through the Gβγ-SNARE interaction is a crucial component of numerous physiological and behavioral processes.

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