scholarly journals The puzzling uniqueness of the heterotrimeric G15 protein and its potential beyond hematopoiesis

2010 ◽  
Vol 44 (5) ◽  
pp. 259-269 ◽  
Author(s):  
Flavia Giannone ◽  
Giorgio Malpeli ◽  
Veronica Lisi ◽  
Silvia Grasso ◽  
Priyanka Shukla ◽  
...  
Keyword(s):  
G Protein ◽  
G Proteins ◽  
Physiological Role ◽  
Cell Types ◽  
Biochemical Properties ◽  
Membrane Receptors ◽  
General Mechanism ◽  
Specific Cell ◽  
Α Subunit ◽  
G Protein Coupled

Heterotrimeric G proteins transduce the signals of the largest family of membrane receptors (G protein-coupled receptors, GPCRs) hence triggering the activation of a wide variety of physiological responses. G15 is a G protein characterized by a number of functional peculiarities that make its signaling exceptional: 1) it can couple a variety of Gs-, Gi/o-, and Gq-linked receptors to phospholipase C activation; 2) relatively to other G proteins, it is poorly affected by β-arrestin-dependent desensitization, the general mechanism that regulates GPCR function and 3) at the protein level, its expression is only detected in highly specific cell types (hematopoietic and epithelial cells). G15 α-subunit displays unique structural and biochemical properties, and is phylogenetically the most recent and divergent component of the Gαq/11 subfamily. All these aspects shed a mysterious light on G15 biological role, which remains substantially elusive. Thus, far, G15 signaling has been analyzed in the context of hematopoiesis. Here, we highlight observations supporting the view that G15 functions may extend further beyond the immune system. In addition, we describe puzzling aspects of G15 signaling that offer a novel perspective in the understanding of its physiological role.

scholarly journals Chemogenetic Tools for Causal Cellular and Neuronal Biology

2018 ◽  
Vol 98 (1) ◽  
pp. 391-418 ◽  
Author(s):  
Deniz Atasoy ◽  
Scott M. Sternson
Keyword(s):  
G Protein ◽  
Ex Vivo ◽  
Cell Types ◽  
Cell Populations ◽  
Specific Cell ◽  
Cellular Processes ◽  
Distinct Cell ◽  
G Protein Coupled ◽  
Pharmacological Control

Chemogenetic technologies enable selective pharmacological control of specific cell populations. An increasing number of approaches have been developed that modulate different signaling pathways. Selective pharmacological control over G protein-coupled receptor signaling, ion channel conductances, protein association, protein stability, and small molecule targeting allows modulation of cellular processes in distinct cell types. Here, we review these chemogenetic technologies and instances of their applications in complex tissues in vivo and ex vivo.

New thoughts on the role of the βγ subunit in G protein signal transduction

2000 ◽  
Vol 78 (5) ◽  
pp. 537-550 ◽  
Author(s):  
Barbara Vanderbeld ◽  
Gregory M Kelly
Keyword(s):  
Signal Transduction ◽  
G Protein ◽  
G Proteins ◽  
G Protein Coupled Receptors ◽  
Limited Information ◽  
Α Subunit ◽  
Downstream Effectors ◽  
Receptor Signal ◽  
G Protein Coupled

Heterotrimeric G proteins are involved in numerous biological processes, where they mediate signal transduction from agonist-bound G-protein-coupled receptors to a variety of intracellular effector molecules and ion channels. G proteins consist of two signaling moieties: a GTP-bound α subunit and a βγ heterodimer. The βγ dimer, recently credited as a significant modulator of G-protein-mediated cellular responses, is postulated to be a major determinant of signaling fidelity between G-protein-coupled receptors and downstream effectors. In this review we have focused on the role of βγ signaling and have included examples to demonstrate the heterogeneity in the heterodimer composition and its implications in signaling fidelity. We also present an overview of some of the effectors regulated by βγ and draw attention to the fact that, although G proteins and their associated receptors play an instrumental role in development, there is rather limited information on βγ signaling in embryogenesis.Key words: G protein, βγ subunit, G-protein-coupled receptor, signal transduction, adenylyl cyclase.

scholarly journals Role of G-proteins in the differentiation of epiphyseal chondrocytes

2014 ◽  
Vol 53 (2) ◽  
pp. R39-R45 ◽  
Author(s):  
Andrei S Chagin ◽  
Henry M Kronenberg
Keyword(s):  
G Protein ◽  
G Proteins ◽  
Growth Plate ◽  
Current Knowledge ◽  
Postnatal Growth ◽  
Chondrocyte Differentiation ◽  
Growth Plate Chondrocytes ◽  
Α Subunit ◽  
G Protein Coupled

Herein, we review the regulation of differentiation of the growth plate chondrocytes by G-proteins. In connection with this, we summarize the current knowledge regarding each family of G-protein α subunit, specifically, Gαs, Gαq/11, Gα12/13, and Gαi/o. We discuss different mechanisms involved in chondrocyte differentiation downstream of G-proteins and different G-protein-coupled receptors (GPCRs) activating G-proteins in the epiphyseal chondrocytes. We conclude that among all G-proteins and GPCRs expressed by chondrocytes, Gαshas the most important role and prevents premature chondrocyte differentiation. Receptor for parathyroid hormone (PTHR1) appears to be the major activator of Gαsin chondrocytes and ablation of either one leads to accelerated chondrocyte differentiation, premature fusion of the postnatal growth plate, and ultimately short stature.

scholarly journals Chemogenetic activation of astrocytes in the hippocampus and cortex changes the transcriptome of microglia and other cell types

2020 ◽  
Author(s):  
Stéphanie Philtjens ◽  
Marion T. Turnbull ◽  
Brian P. Thedy ◽  
Younghye Moon ◽  
Jungsu Kim
Keyword(s):  
Single Cell ◽  
G Protein ◽  
Low Density Lipoprotein ◽  
Ion Homeostasis ◽  
Density Lipoprotein ◽  
Cell Types ◽  
Designer Drugs ◽  
Specific Cell ◽  
G Protein Coupled

AbstractAstrocytes are the most common glial cell type in the brain, yet, it is still not clear how their activation affects the transcriptome of other brain cells such as microglia and neurons. Engineered G protein-coupled receptors called Designer Receptors Exclusively Activated by Designer Drugs (DREADDS) make it possible to selectively activate specific cell types, such as neurons and astrocytes. By combining the selective activation of astrocytes with single cell RNA sequencing, we were able to study transcriptional changes that occur in response to the activation of astrocytes at the single cell level. Interestingly, our data shows that long-term activation of astrocytes in healthy mice results in dramatic alteration in the transcriptome of astrocytes and microglia. Genes that were differentially expressed in these Gq-DREADD-activated astrocytes were involved in neurogenesis and low density lipoprotein particle biology, while those in the microglia were involved in the response to lipoproteins, and the migration and chemotaxis of immune cells. Furthermore, network analysis showed that Gq-DREADD-mediated activation in astrocytes resulted in an upregulation of genes involved in the G protein-coupled receptor signaling pathway and calcium ion homeostasis. This confirmed the activation of astrocytes through the expressed DREADDS. Our findings show the importance of considering the transcriptomic alteration in microglia and neurons after the activation of astrocytes in in vivo models. Therefore, our data will serve as a resource for the broader neuroscience community.

Selective inactivation of guanine-nucleotide-binding regulatory protein (G-protein) α and βγ subunits by urea

2001 ◽  
Vol 354 (2) ◽  
pp. 337-344 ◽  
Author(s):  
William K. LIM ◽  
Richard R. NEUBIG
Keyword(s):  
G Protein ◽  
G Proteins ◽  
Regulatory Protein ◽  
Significant Loss ◽  
Membrane Extraction ◽  
Α Subunit ◽  
Mammalian Cell Lines ◽  
Membrane Bound ◽  
Guanine Nucleotide Binding ◽  
G Protein Coupled

G-protein-coupled receptors activate signal-transducing G-proteins, which consist of an α subunit and a βγ dimer. Membrane extraction with 5–7M urea has been used to uncouple receptors from endogenous G-proteins to permit reconstitution with purified G-proteins. We show that αi subunits are inactivated with 5M urea whereas the βγ dimer requires at least 7M urea for its inactivation. There is no significant loss of receptors. Surprisingly, Western-blot analysis indicates that the urea-denatured αi subunit remains mostly membrane-bound and that β is only partially removed. After 7M urea treatment, both αi1 and βγ subunits are required to restore high-affinity agonist binding and receptor-catalysed guanosine 5′-[γ-thio]triphosphate binding. We demonstrate the generality of this approach for four Gi-coupled receptors (α2A-adrenergic, adenosine A1, 5-hydroxytryptamine1A and µ-opioid) expressed in insect cells and two mammalian cell lines. Thus a selectivity of urea for G-protein α versus βγ subunits is established in both concentration and mechanism.

Use of DREADD Technology to Identify Novel Targets for Antidiabetic Drugs

2021 ◽  
Vol 61 (1) ◽  
pp. 421-440
Author(s):  
Lei Wang ◽  
Lu Zhu ◽  
Jaroslawna Meister ◽  
Derek B.J. Bone ◽  
Sai P. Pydi ◽  
...  
Keyword(s):  
G Protein ◽  
G Proteins ◽  
Metabolic Diseases ◽  
Cell Types ◽  
Membrane Receptors ◽  
Designer Drug ◽  
Heterotrimeric G Proteins ◽  
Distinct Cell Type ◽  
The Individual

G protein–coupled receptors (GPCRs) form a superfamily of plasma membrane receptors that couple to four major families of heterotrimeric G proteins, Gs, Gi, Gq, and G12. GPCRs represent excellent targets for drug therapy. Since the individual GPCRs are expressed by many different cell types, the in vivo metabolic roles of a specific GPCR expressed by a distinct cell type are not well understood. The development of designer GPCRs known as DREADDs (designer receptors exclusively activated by a designer drug) that selectively couple to distinct classes of heterotrimeric G proteins has greatly facilitated studies in this area. This review focuses on the use of DREADD technology to explore the physiological and pathophysiological roles of distinct GPCR/G protein cascades in several metabolically important cell types. The novel insights gained from these studies should stimulate the development of GPCR-based treatments for major metabolic diseases such as type 2 diabetes and obesity.

G-protein-coupled receptors, channels, and Na+–H+ exchanger in nuclear membranes of heart, hepatic, vascular endothelial, and smooth muscle cellsThis paper is one of a selection of papers published in this Special Issue, entitled The Nucleus: A Cell Within A Cell.

2006 ◽  
Vol 84 (3-4) ◽  
pp. 431-441 ◽  
Author(s):  
Ghassan Bkaily ◽  
Moni Nader ◽  
Levon Avedanian ◽  
Sana Choufani ◽  
Danielle Jacques ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
G Protein ◽  
Cell Types ◽  
G Protein Coupled Receptors ◽  
Specific Cell ◽  
Endothelin 1 ◽  
Nuclear Membranes ◽  
Ionic Transporters ◽  
A Cell ◽  
G Protein Coupled

The action of several peptides and drugs is thought to be primarily dependent on their interactions with specific cell surface G-protein-coupled receptors and ionic transporters such as channels and exchangers. Recent development of 3-D confocal microscopy allowed several laboratories, including ours, to identify and study the localization of receptors, channels, and exchangers at the transcellular level of several cell types. Using this technique, we demonstrated in the nuclei of several types of cells the presence of Ca2+ channels as well as Na+–H+ exchanger and receptors such as endothelin-1 and angiotensin II receptors. Stimulation of these nuclear membrane G-protein-coupled receptors induced an increase of nuclear Ca2+. Our results suggest that, similar to the plasma membrane, nuclear membranes possess channels, exchangers and receptors such as those for endothelin-1 and angiotensin II, and that the nucleus seems to be a cell within a cell. This article will emphasize these findings.

scholarly journals Integration and Spatial Organization of Signaling by G Protein-Coupled Receptor Homo- and Heterodimers

Biomolecules ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1828
Author(s):  
Roberto Maggio ◽  
Irene Fasciani ◽  
Marco Carli ◽  
Francesco Petragnano ◽  
Francesco Marampon ◽  
...  
Keyword(s):  
G Protein ◽  
Information Exchange ◽  
Cell Biology ◽  
Spatial Organization ◽  
Second Messengers ◽  
Cell Communication ◽  
Physiological Role ◽  
Membrane Receptors ◽  
Structural Basis ◽  
G Protein Coupled

Information flow from a source to a receiver becomes informative when the recipient can process the signal into a meaningful form. Information exchange and interpretation is essential in biology and understanding how cells integrate signals from a variety of information-coding molecules into complex orchestrated responses is a major challenge for modern cell biology. In complex organisms, cell to cell communication occurs mostly through neurotransmitters and hormones, and receptors are responsible for signal recognition at the membrane level and information transduction inside the cell. The G protein-coupled receptors (GPCRs) are the largest family of membrane receptors, with nearly 800 genes coding for these proteins. The recognition that GPCRs may physically interact with each other has led to the hypothesis that their dimeric state can provide the framework for temporal coincidence in signaling pathways. Furthermore, the formation of GPCRs higher order oligomers provides the structural basis for organizing distinct cell compartments along the plasma membrane where confined increases in second messengers may be perceived and discriminated. Here, we summarize evidence that supports these conjectures, fostering new ideas about the physiological role played by receptor homo- and hetero-oligomerization in cell biology.

scholarly journals Proton-sensing G protein-coupled receptors: detectors of tumor acidosis and candidate drug targets

2020 ◽  
Vol 12 (6) ◽  
pp. 523-532 ◽  
Author(s):  
Paul A Insel ◽  
Krishna Sriram ◽  
Cristina Salmerón ◽  
Shu Z Wiley
Keyword(s):  
G Protein ◽  
Drug Targets ◽  
Tumor Biology ◽  
Cell Types ◽  
G Protein Coupled Receptors ◽  
Specific Cell ◽  
Tumor Microenvironments ◽  
Candidate Drug ◽  
Survival And Growth ◽  
G Protein Coupled

Cells in tumor microenvironments (TMEs) use several mechanisms to sense their low pH (<7.0), including via proton-sensing G protein-coupled receptors (psGPCRs): GPR4, GPR65/TDAG8, GPR68/OGR1 and GPR132/G2A. Numerous cancers have increased expression of psGPCRs. The psGPCRs may contribute to features of the malignant phenotype via actions on specific cell-types in the TME and thereby promote tumor survival and growth. Here, we review data regarding psGPCR expression in tumors and cancer cells, impact of psGPCRs on survival in solid tumors and a bioinformatics approach to infer psGPCR expression in cell types in the TME. New tools are needed to help define contributions of psGPCRs in tumor biology and to identify potentially novel therapeutic agents for a variety of cancers.

scholarly journals Knockout of the LRRC26 subunit reveals a primary role of LRRC26-containing BK channels in secretory epithelial cells

2017 ◽  
Vol 114 (18) ◽  
pp. E3739-E3747 ◽  
Author(s):  
Chengtao Yang ◽  
Vivian Gonzalez-Perez ◽  
Taro Mukaibo ◽  
James E. Melvin ◽  
Xiao-Ming Xia ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Physiological Role ◽  
Cell Types ◽  
Bk Channels ◽  
Specific Cell ◽  
Primary Role ◽  
Cellular Functions ◽  
Α Subunit ◽  
Voltage Dependent

Leucine-rich-repeat-containing protein 26 (LRRC26) is the regulatory γ1 subunit of Ca2+- and voltage-dependent BK-type K+ channels. BK channels that contain LRRC26 subunits are active near normal resting potentials even without Ca2+, suggesting they play unique physiological roles, likely limited to very specific cell types and cellular functions. By using Lrrc26 KO mice with a β-gal reporter, Lrrc26 promoter activity is found in secretory epithelial cells, especially acinar epithelial cells in lacrimal and salivary glands, and also goblet and Paneth cells in intestine and colon, although absent from neurons. We establish the presence of LRRC26 protein in eight secretory tissues or tissues with significant secretory epithelium and show that LRRC26 protein coassembles with the pore-forming BK α-subunit in at least three tissues: lacrimal gland, parotid gland, and colon. In lacrimal, parotid, and submandibular gland acinar cells, LRRC26 KO shifts BK gating to be like α-subunit-only BK channels. Finally, LRRC26 KO mimics the effect of SLO1/BK KO in reducing [K+] in saliva. LRRC26-containing BK channels are competent to contribute to resting K+ efflux at normal cell membrane potentials with resting cytosolic Ca2+ concentrations and likely play a critical physiological role in supporting normal secretory function in all secretory epithelial cells.

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