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.

G-protein-coupled receptor structure, ligand binding and activation as studied by solid-state NMR spectroscopy

2013 ◽  
Vol 450 (3) ◽  
pp. 443-457 ◽  
Author(s):  
Xiaoyan Ding ◽  
Xin Zhao ◽  
Anthony Watts
Keyword(s):  
Protein Structure ◽  
Solid State ◽  
Ligand Binding ◽  
G Protein ◽  
Solid State Nmr ◽  
Regulatory Elements ◽  
Membrane Receptors ◽  
Structural Basis ◽  
Signalling Molecules ◽  
G Protein Coupled

GPCRs (G-protein-coupled receptors) are versatile signalling molecules at the cell surface and make up the largest and most diverse family of membrane receptors in the human genome. They convert a large variety of extracellular stimuli into intracellular responses through the activation of heterotrimeric G-proteins, which make them key regulatory elements in a broad range of normal and pathological processes, and are therefore one of the most important targets for pharmaceutical drug discovery. Knowledge of a GPCR structure enables us to gain a mechanistic insight into its function and dynamics, and further aid rational drug design. Despite intensive research carried out over the last three decades, resolving the structural basis of GPCR function is still a major activity. The crystal structures obtained in the last 5 years provide the first opportunity to understand how protein structure dictates the unique functional properties of these complex signalling molecules. However, owing to the intrinsic hydrophobicity, flexibility and instability of membrane proteins, it is still a challenge to crystallize GPCRs, and, when this is possible, it is no longer in its native membrane environment and no longer without modification. Furthermore, the conformational change of the transmembrane α-helices associated with the structure activation increases the difficulty of capturing the activation state of a GPCR to a higher resolution by X-ray crystallography. On the other hand, solid-state NMR may offer a unique opportunity to study membrane protein structure, ligand binding and activation at atomic resolution in the native membrane environment, as well as described functionally significant dynamics. In the present review, we discuss some recent achievements of solid-state NMR for understanding GPCRs, the largest mammalian proteome at ~1% of the total expressed proteins. Structural information, details of determination, details of ligand conformations and the consequences of ligand binding to initiate activation can all be explored with solid-state NMR.

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.

Recent Advances of Small Molecular Regulators Targeting G Protein- Coupled Receptors Family for Oncology Immunotherapy

2019 ◽  
Vol 19 (16) ◽  
pp. 1464-1483 ◽  
Author(s):  
Peng He ◽  
Wenbo Zhou ◽  
Mingyao Liu ◽  
Yihua Chen
Keyword(s):  
G Protein ◽  
Cell Biology ◽  
Immune Cell ◽  
G Protein Coupled Receptors ◽  
Treatment Modalities ◽  
Immune Checkpoints ◽  
Considerable Proportion ◽  
Prostaglandin E ◽  
Recent Advances ◽  
G Protein Coupled

The great clinical success of chimeric antigen receptor T cell (CAR-T) and PD-1/PDL-1 inhibitor therapies suggests the drawing of a cancer immunotherapy age. However, a considerable proportion of cancer patients currently receive little benefit from these treatment modalities, indicating that multiple immunosuppressive mechanisms exist in the tumor microenvironment. In this review, we mainly discuss recent advances in small molecular regulators targeting G Protein-Coupled Receptors (GPCRs) that are associated with oncology immunomodulation, including chemokine receptors, purinergic receptors, prostaglandin E receptor EP4 and opioid receptors. Moreover, we outline how they affect tumor immunity and neoplasia by regulating immune cell recruitment and modulating tumor stromal cell biology. We also summarize the data from recent clinical advances in small molecular regulators targeting these GPCRs, in combination with immune checkpoints blockers, such as PD-1/PDL-1 and CTLA4 inhibitors, for cancer treatments.

scholarly journals Human Homologs of the Putative G Protein-Coupled Membrane Progestin Receptors (mPRα, β, and γ) Localize to the Endoplasmic Reticulum and Are Not Activated by Progesterone

2006 ◽  
Vol 20 (12) ◽  
pp. 3146-3164 ◽  
Author(s):  
Tom Krietsch ◽  
Maria Sofia Fernandes ◽  
Jukka Kero ◽  
Ralf Lösel ◽  
Maria Heyens ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
G Protein ◽  
Cell Lines ◽  
Spotted Seatrout ◽  
Membrane Receptors ◽  
Takifugu Rubripes ◽  
Camp Production ◽  
Intact Cells ◽  
Progestin Receptors ◽  
G Protein Coupled

Abstract The steroid hormone progesterone exerts pleiotrophic functions in many cell types. Although progesterone controls transcriptional activation through binding to its nuclear receptors, it also initiates rapid nongenomic signaling events. Recently, three putative membrane progestin receptors (mPRα, β, and γ) with structural similarity to G protein-coupled receptors have been identified. These mPR isoforms are expressed in a tissue-specific manner and belong to the larger, highly conserved family of progestin and adiponectin receptors found in plants, eubacteria, and eukaryotes. The fish mPRα has been reported to mediate progesterone-dependent MAPK activation and inhibition of cAMP production through coupling to an inhibitory G protein. To functionally characterize the human homologs, we established human embryonic kidney 293 and MDA-MB-231 cell lines that stably express human mPRα, β, or γ. For comparison, we also established cell lines expressing the mPRα cloned from the spotted seatrout (Cynoscion nebulosus) and Japanese pufferfish (Takifugu rubripes). Surprisingly, we found no evidence that human or fish mPRs regulate cAMP production or MAPK (ERK1/2 or p38) activation upon progesterone stimulation. Furthermore, the mPRs did not couple to a highly promiscuous G protein subunit, Gαq5i, in transfection studies or provoke Ca2+ mobilization in response to progesterone. Finally, we demonstrate that transfected mPRs, as well as endogenous human mPRα, localize to the endoplasmic reticulum, and that their expression does not lead to increased progestin binding either in membrane preparations or in intact cells. Our results therefore do not support the concept that mPRs are plasma membrane receptors involved in transducing nongenomic progesterone actions.

scholarly journals Imaging of persistent cAMP signaling by internalized G protein-coupled receptors

2010 ◽  
Vol 45 (1) ◽  
pp. 1-8 ◽  
Author(s):  
Davide Calebiro ◽  
Viacheslav O Nikolaev ◽  
Martin J Lohse
Keyword(s):  
G Protein ◽  
Intracellular Signaling ◽  
Current Model ◽  
Living Cells ◽  
G Protein Coupled Receptors ◽  
Membrane Receptors ◽  
Optical Methods ◽  
Camp Signaling ◽  
Gpcr Signaling ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs) are the largest family of plasma membrane receptors. They mediate the effects of several endogenous cues and serve as important pharmacological targets. Although many biochemical events involved in GPCR signaling have been characterized in great detail, little is known about their spatiotemporal dynamics in living cells. The recent advent of optical methods based on fluorescent resonance energy transfer allows, for the first time, to directly monitor GPCR signaling in living cells. Utilizing these methods, it has been recently possible to show that the receptors for two protein/peptide hormones, the TSH and the parathyroid hormone, continue signaling to cAMP after their internalization into endosomes. This type of intracellular signaling is persistent and apparently triggers specific cellular outcomes. Here, we review these recent data and explain the optical methods used for such studies. Based on these findings, we propose a revision of the current model of the GPCR–cAMP signaling pathway to accommodate receptor signaling at endosomes.

A generic microfluidic biosensor of G protein-coupled receptor activation – impedance measurements of reversible morphological changes of reverse transfected HEK293 cells on microelectrodes

RSC Advances ◽  
2015 ◽  
Vol 5 (65) ◽  
pp. 52563-52570 ◽  
Author(s):  
Saurabh K. Srivastava ◽  
Rajesh Ramaneti ◽  
Margriet Roelse ◽  
Hien Duy Tong ◽  
Elwin X. Vrouwe ◽  
...  
Keyword(s):  
G Protein ◽  
Morphological Changes ◽  
Receptor Activation ◽  
Membrane Receptors ◽  
Hek293 Cells ◽  
G Protein Coupled Receptor ◽  
Impedance Measurements ◽  
Transfected Cells ◽  
Microfluidic Biosensor ◽  
G Protein Coupled

Flowcell with micro-IDEs (250–500 μm) covered with both stable and reverse transfected cells overexpressing membrane receptors to demonstrate impedance responses to serial injections of analyte.

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