Consequences of lipid raft association on G-protein-coupled receptor function.

2005 ◽  
Vol 72 ◽  
pp. 151-164 ◽  
Author(s):  
Anja Becher ◽  
R. A. Jeffrey McIlhinney
Keyword(s):  
G Protein ◽  
Lipid Rafts ◽  
Lipid Raft ◽  
Neurological Disorders ◽  
G Protein Coupled Receptors ◽  
Membrane Microdomains ◽  
Pharmaceutical Drug ◽  
Cellular Processes ◽  
G Protein Coupled ◽  
Specific Membrane

GPCRs (G-protein-coupled receptors) play key roles in many cellular processes, and malfunction may lead to a range of pathologies, including psychiatric and neurological disorders. It is therefore not surprising that this group of receptors supplies a majority of the targets for pharmaceutical drug development. Despite their importance, the mechanisms that regulate their function and signalling still remain only partially understood. Recently, it has become evident that a subset of GPCRs is not homogeneously distributed in the plasma membrane, but localizes instead to specific membrane microdomains known as lipid rafts. Lipid rafts are characterized by their enrichment in cholesterol and sphingolipids, and have been suggested to serve as platforms for a range of cellular signalling complexes. In the present review, we will be discussing the effects of the lipid raft environment on trafficking, signalling and internalization of raft-associated GPCRs.

Compartmentation of G-protein-coupled receptors and their signalling components in lipid rafts and caveolae

2005 ◽  
Vol 33 (5) ◽  
pp. 1131-1134 ◽  
Author(s):  
P.A. Insel ◽  
B.P. Head ◽  
H.H. Patel ◽  
D.M. Roth ◽  
R.A. Bundey ◽  
...  
Keyword(s):  
G Protein ◽  
Lipid Rafts ◽  
Plasma Membranes ◽  
Subcellular Fractionation ◽  
G Protein Coupled Receptors ◽  
Membrane Microdomains ◽  
Adult Cardiac Myocytes ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide ◽  
G Protein Coupled

G-protein-coupled receptors (GPCRs) and post-GPCR signalling components are expressed at low overall abundance in plasma membranes, yet they evoke rapid, high-fidelity responses. Considerable evidence suggests that GPCR signalling components are organized together in membrane microdomains, in particular lipid rafts, enriched in cholesterol and sphingolipids, and caveolae, a subset of lipid rafts that also possess the protein caveolin, whose scaffolding domain may serve as an anchor for signalling components. Caveolae were originally identified based on their morphological appearance but their role in compartmentation of GPCR signalling has been primarily studied by biochemical techniques, such as subcellular fractionation and immunoprecipitation. Our recent studies obtained using both microscopic and biochemical methods with adult cardiac myocytes show expression of caveolin not only in surface sarcolemmal domains but also at, or close to, internal regions located at transverse tubules/sarcoplasmic reticulum. Other results show co-localization in lipid rafts/caveolae of AC (adenylyl cyclase), in particular AC6, certain GPCRs, G-proteins and eNOS (endothelial nitric oxide synthase; NOS3), which generates NO, a modulator of AC6. Existence of multiple caveolin-rich microdomains and their expression of multiple modulators of signalling strengthen the evidence that caveolins and lipid rafts/caveolae organize and regulate GPCR signal transduction in eukaryotic cells.

scholarly journals G-protein coupled receptors in lipid rafts and caveolae: how, when and why do they go there?

2004 ◽  
Vol 32 (2) ◽  
pp. 325-338 ◽  
Author(s):  
B Chini ◽  
M Parenti
Keyword(s):  
G Protein ◽  
Lipid Rafts ◽  
G Protein Coupled Receptors ◽  
Fine Tuning ◽  
Membrane Microdomains ◽  
Signalling Molecules ◽  
Cell Functions ◽  
Experimental Approaches ◽  
G Protein Coupled

This review describes the advances in our understanding of the role of G-protein coupled receptor (GPCR) localisation in membrane microdomains known as lipid rafts and caveolae. The growing interest in these specialised regions is due to the recognition that they are involved in the regulation of a number of cell functions, including the fine-tuning of various signalling molecules. As a number of GPCRs have been found to be enriched in lipid rafts and/or caveolae by means of different experimental approaches, we first discuss the pitfalls and uncertainties related to the use of these different procedures. We then analyse the addressing signals that drive and/or stabilise GPCRs in lipid rafts and caveolae, and explore the role of rafts/caveolae in regulating GPCR trafficking, particularly in receptor exo- and endocytosis. Finally, we review the growing evidence that lipid rafts and caveolae participate in the regulation of GPCR signalling by affecting both signalling selectivity and coupling efficacy.

scholarly journals Heteromerization of G Protein-Coupled Receptors: Relevance to Neurological Disorders and Neurotherapeutics

2010 ◽  
Vol 9 (5) ◽  
pp. 636-650 ◽  
Author(s):  
Laura Albizu ◽  
Jose L. Moreno ◽  
Javier Gonzalez-Maeso ◽  
Stuart C. Sealfon
Keyword(s):  
G Protein ◽  
Neurological Disorders ◽  
G Protein Coupled Receptors ◽  
G Protein Coupled

scholarly journals Function of Platelet Glycosphingolipid Microdomains/Lipid Rafts

2020 ◽  
Vol 21 (15) ◽  
pp. 5539
Author(s):  
Keisuke Komatsuya ◽  
Kei Kaneko ◽  
Kohji Kasahara
Keyword(s):  
Lipid Rafts ◽  
Platelet Adhesion ◽  
G Protein Coupled Receptors ◽  
Clot Retraction ◽  
Functional Roles ◽  
Glycoprotein Vi ◽  
Cellular Processes ◽  
Specific Proteins ◽  
G Protein Coupled ◽  
Collagen Receptor

Lipid rafts are dynamic assemblies of glycosphingolipids, sphingomyelin, cholesterol, and specific proteins which are stabilized into platforms involved in the regulation of vital cellular processes. The rafts at the cell surface play important functions in signal transduction. Recent reports have demonstrated that lipid rafts are spatially and compositionally heterogeneous in the single-cell membrane. In this review, we summarize our recent data on living platelets using two specific probes of raft components: lysenin as a probe of sphingomyelin-rich rafts and BCθ as a probe of cholesterol-rich rafts. Sphingomyelin-rich rafts that are spatially and functionally distinct from the cholesterol-rich rafts were found at spreading platelets. Fibrin is translocated to sphingomyelin-rich rafts and platelet sphingomyelin-rich rafts act as platforms where extracellular fibrin and intracellular actomyosin join to promote clot retraction. On the other hand, the collagen receptor glycoprotein VI is known to be translocated to cholesterol-rich rafts during platelet adhesion to collagen. Furthermore, the functional roles of platelet glycosphingolipids and platelet raft-binding proteins including G protein-coupled receptors, stomatin, prohibitin, flotillin, and HflK/C-domain protein family, tetraspanin family, and calcium channels are discussed.

scholarly journals Mechanisms of cross-talk between G-protein-coupled receptors resulting in enhanced release of intracellular Ca2+

2003 ◽  
Vol 374 (2) ◽  
pp. 281-296 ◽  
Author(s):  
Tim D. WERRY ◽  
Graeme F. WILKINSON ◽  
Gary B. WILLARS
Keyword(s):  
G Protein ◽  
Cross Talk ◽  
Cell Function ◽  
Feedback Regulation ◽  
G Protein Coupled Receptors ◽  
Negative Feedback Regulation ◽  
Cellular Processes ◽  
Heterologous Desensitization ◽  
G Protein Coupled

Alteration in [Ca2+]i (the intracellular concentration of Ca2+) is a key regulator of many cellular processes. To allow precise regulation of [Ca2+]i and a diversity of signalling by this ion, cells possess many mechanisms by which they are able to control [Ca2+]i both globally and at the subcellular level. Among these are many members of the superfamily of GPCRs (G-protein-coupled receptors), which are characterized by the presence of seven transmembrane domains. Typically, those receptors able to activate PLC (phospholipase C) enzymes cause release of Ca2+ from intracellular stores and influence Ca2+ entry across the plasma membrane. It has been well documented that Ca2+ signalling by one type of GPCR can be influenced by stimulation of a different type of GPCR. Indeed, many studies have demonstrated heterologous desensitization between two different PLC-coupled GPCRs. This is not surprising, given our current understanding of negative-feedback regulation and the likely shared components of the signalling pathway. However, there are also many documented examples of interactions between GPCRs, often coupling preferentially to different signalling pathways, which result in a potentiation of Ca2+ signalling. Such interactions have important implications for both the control of cell function and the interpretation of in vitro cell-based assays. However, there is currently no single mechanism that adequately accounts for all examples of this type of cross-talk. Indeed, many studies either have not addressed this issue or have been unable to determine the mechanism(s) involved. This review seeks to explore a range of possible mechanisms to convey their potential diversity and to provide a basis for further experimental investigation.

Compartmentation of G-protein-coupled receptors and their signalling components in lipid rafts and caveolae

2005 ◽  
Vol 33 (5) ◽  
pp. 1131 ◽  
Author(s):  
B.P. Head ◽  
P.A. Insel ◽  
H.H. Patel ◽  
D.M. Roth ◽  
R.A. Bundey ◽  
...  
Keyword(s):  
G Protein ◽  
Lipid Rafts ◽  
G Protein Coupled Receptors ◽  
G Protein Coupled

scholarly journals Ligand Docking Methods to Recognize Allosteric Inhibitors for G-protein Coupled Receptors

2020 ◽  
Author(s):  
K Harini ◽  
S Jayashree ◽  
Vikas Tiwari ◽  
Sneha Vishwanath ◽  
Ramanathan Sowdhamini
Keyword(s):  
Binding Site ◽  
G Protein ◽  
Drug Targets ◽  
G Protein Coupled Receptors ◽  
Ligand Docking ◽  
Computational Docking ◽  
Cellular Processes ◽  
Activation Mechanisms ◽  
Approved Drugs ◽  
G Protein Coupled

G-protein coupled receptors (GPCRs) are large protein families known to be important in many cellular processes. They are well known for their allosteric activation mechanisms. They are drug targets for several FDA-approved drugs. We have investigated the diversity of the ligand binding site for these class of proteins against their cognate ligands using computational docking, even if their structures are known in the ligand-complexed form. The cognate ligand of some of these receptors dock at allosteric binding site, with better score than the binding at the conservative site. Further, ligands obtained from GLASS database, which consists of experimentally verified GPCR ligands, also show allosteric binding to GPCRs. The allosteric binders show strong affinity to the binding site, though the residues at the binding site are not conserved across GPCR subfamilies.

scholarly journals Ligand Docking Methods to Recognize Allosteric Inhibitors for G-Protein-Coupled Receptors

2021 ◽  
Vol 15 ◽  
pp. 117793222110377
Author(s):  
K Harini ◽  
S Jayashree ◽  
Vikas Tiwari ◽  
Sneha Vishwanath ◽  
Ramanathan Sowdhamini
Keyword(s):  
Binding Site ◽  
G Protein ◽  
Drug Targets ◽  
Drug Binding ◽  
G Protein Coupled Receptors ◽  
Ligand Docking ◽  
Amino Acid Residues ◽  
Computational Docking ◽  
Cellular Processes ◽  
G Protein Coupled

G-protein-coupled receptors (GPCRs) are membrane proteins which play an important role in many cellular processes and are excellent drug targets. Despite the existence of several US Food and Drug Administration (FDA)-approved GPCR-targeting drugs, there is a continuing challenge of side effects owing to the nonspecific nature of drug binding. We have investigated the diversity of the ligand binding site for this class of proteins against their cognate ligands using computational docking, even if their structures are known already in the ligand-complexed form. The cognate ligand of some of these receptors dock at allosteric binding site with better score than the binding at the conservative site. Interestingly, amino acid residues at such allosteric binding site are not conserved across GPCR subfamilies. Such a computational approach can assist in the prediction of specific allosteric binders for GPCRs.

scholarly journals G-Protein-Coupled Receptors in CNS: A Potential Therapeutic Target for Intervention in Neurodegenerative Disorders and Associated Cognitive Deficits

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 506 ◽  
Author(s):  
Shofiul Azam ◽  
Md. Ezazul Haque ◽  
Md. Jakaria ◽  
Song-Hee Jo ◽  
In-Su Kim ◽  
...  
Keyword(s):  
G Protein ◽  
Cognitive Deficits ◽  
Therapeutic Target ◽  
Neurological Disorders ◽  
Symptomatic Relief ◽  
Underlying Disease ◽  
G Protein Coupled Receptors ◽  
Potential Therapeutic Target ◽  
G Protein Coupled ◽  
Insight Into

Neurodegenerative diseases are a large group of neurological disorders with diverse etiological and pathological phenomena. However, current therapeutics rely mostly on symptomatic relief while failing to target the underlying disease pathobiology. G-protein-coupled receptors (GPCRs) are one of the most frequently targeted receptors for developing novel therapeutics for central nervous system (CNS) disorders. Many currently available antipsychotic therapeutics also act as either antagonists or agonists of different GPCRs. Therefore, GPCR-based drug development is spreading widely to regulate neurodegeneration and associated cognitive deficits through the modulation of canonical and noncanonical signals. Here, GPCRs’ role in the pathophysiology of different neurodegenerative disease progressions and cognitive deficits has been highlighted, and an emphasis has been placed on the current pharmacological developments with GPCRs to provide an insight into a potential therapeutic target in the treatment of neurodegeneration.

The use of fluorescence correlation spectroscopy to characterise the molecular mobility of G protein-coupled receptors in membrane microdomains: an update

2021 ◽  
Vol 49 (4) ◽  
pp. 1547-1554
Author(s):  
Laura E. Kilpatrick ◽  
Stephen J. Hill
Keyword(s):  
G Protein ◽  
Fluorescence Correlation Spectroscopy ◽  
Molecular Mechanisms ◽  
Short Review ◽  
Correlation Spectroscopy ◽  
G Protein Coupled Receptors ◽  
Membrane Microdomains ◽  
Sensitivity Threshold ◽  
Fluorescence Correlation ◽  
G Protein Coupled

It has become increasingly apparent that some G protein-coupled receptors (GPCRs) are not homogeneously expressed within the plasma membrane but may instead be organised within distinct signalling microdomains. These microdomains localise GPCRs in close proximity with other membrane proteins and intracellular signalling partners and could have profound implications for the spatial and temporal control of downstream signalling. In order to probe the molecular mechanisms that govern GPCR pharmacology within these domains, fluorescence techniques with effective single receptor sensitivity are required. Of these, fluorescence correlation spectroscopy (FCS) is a technique that meets this sensitivity threshold. This short review will provide an update of the recent uses of FCS based techniques in conjunction with GPCR subtype selective fluorescent ligands to characterise dynamic ligand–receptor interactions in whole cells and using purified GPCRs.

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