scholarly journals G-protein-coupled receptors, cholesterol and palmitoylation: facts about fats

2009 ◽  
Vol 42 (5) ◽  
pp. 371-379 ◽  
Author(s):  
Bice Chini ◽  
Marco Parenti
Keyword(s):  
Plasma Membrane ◽  
G Protein ◽  
G Protein Coupled Receptors ◽  
Membrane Domains ◽  
Functional Features ◽  
Gpcr Structure ◽  
Carboxyl Terminal ◽  
The Impact ◽  
G Protein Coupled ◽  
Partner Proteins

G-protein-coupled receptors (GPCRs) are integral membrane proteins, hence it is not surprising that a number of their structural and functional features are modulated by both proteins and lipids. The impact of interacting proteins and lipids on the assembly and signalling of GPCRs has been extensively investigated over the last 20–30 years, and a further impetus has been given by the proposal that GPCRs and/or their immediate signalling partners (G proteins) can partition within plasma membrane domains, termed rafts and caveolae, enriched in glycosphingolipids and cholesterol. The high content of these specific lipids, in particular of cholesterol, in the vicinity of GPCR transmembranes can affect GPCR structure and/or function. In addition, most GPCRs are post-translationally modified with one or more palmitic acid(s), a 16-carbon saturated fatty acid, covalently bound to cysteine(s) localised in the carboxyl-terminal cytoplasmic tail. The insertion of palmitate into the cytoplasmic leaflet of the plasma membrane can create a fourth loop, thus profoundly affecting GPCR structure and hence the interactions with intracellular partner proteins. This review briefly highlights how lipids of the membrane and the receptor themselves can influence GPCR organisation and functioning.

scholarly journals Misfolded G Protein-Coupled Receptors and Endocrine Disease. Molecular Mechanisms and Therapeutic Prospects

2021 ◽  
Vol 22 (22) ◽  
pp. 12329
Author(s):  
Alfredo Ulloa-Aguirre ◽  
Teresa Zariñán ◽  
Eduardo Jardón-Valadez
Keyword(s):  
Plasma Membrane ◽  
G Protein ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
G Protein Coupled Receptors ◽  
Membrane Receptors ◽  
Therapeutic Interventions ◽  
Endocrine Function ◽  
Receptor Protein ◽  
G Protein Coupled

Misfolding of G protein-coupled receptors (GPCRs) caused by mutations frequently leads to disease due to intracellular trapping of the conformationally abnormal receptor. Several endocrine diseases due to inactivating mutations in GPCRs have been described, including X-linked nephrogenic diabetes insipidus, thyroid disorders, familial hypocalciuric hypercalcemia, obesity, familial glucocorticoid deficiency [melanocortin-2 receptor, MC2R (also known as adrenocorticotropin receptor, ACTHR), and reproductive disorders. In these mutant receptors, misfolding leads to endoplasmic reticulum retention, increased intracellular degradation, and deficient trafficking of the abnormal receptor to the cell surface plasma membrane, causing inability of the receptor to interact with agonists and trigger intracellular signaling. In this review, we discuss the mechanisms whereby mutations in GPCRs involved in endocrine function in humans lead to misfolding, decreased plasma membrane expression of the receptor protein, and loss-of-function diseases, and also describe several experimental approaches employed to rescue trafficking and function of the misfolded receptors. Special attention is given to misfolded GPCRs that regulate reproductive function, given the key role played by these particular membrane receptors in sexual development and fertility, and recent reports on promising therapeutic interventions targeting trafficking of these defective proteins to rescue completely or partially their normal function.

scholarly journals Mammalian Type I Gonadotropin-Releasing Hormone Receptors Undergo Slow, Constitutive, Agonist-Independent Internalization

Endocrinology ◽  
2007 ◽  
Vol 149 (3) ◽  
pp. 1415-1422 ◽  
Author(s):  
Adam J. Pawson ◽  
Elena Faccenda ◽  
Stuart Maudsley ◽  
Zhi-Liang Lu ◽  
Zvi Naor ◽  
...  
Keyword(s):  
G Protein ◽  
Regulatory Elements ◽  
Gnrh Receptor ◽  
G Protein Coupled Receptors ◽  
Receptor Internalization ◽  
Type I ◽  
Receptor Desensitization ◽  
Gnrh Receptors ◽  
Carboxyl Terminal ◽  
G Protein Coupled

Regulatory elements present in the cytoplasmic carboxyl-terminal tails of G protein-coupled receptors contribute to agonist-dependent receptor desensitization, internalization, and association with accessory proteins such as β-arrestin. The mammalian type I GnRH receptors are unique among the rhodopsin-like G protein-coupled receptors because they lack a cytoplasmic carboxyl-terminal tail. In addition, they do not recruit β-arrestin, nor do they undergo rapid desensitization. By measuring the internalization of labeled GnRH agonists, previous studies have reported that mammalian type I GnRH receptors undergo slow agonist-dependent internalization. In the present study, we have measured the internalization of epitope-tagged GnRH receptors, both in the absence and presence of GnRH stimulation. We demonstrate that mammalian type I GnRH receptors exhibit a low level of constitutive agonist-independent internalization. Stimulation with GnRH agonist did not significantly enhance the level of receptor internalization above the constitutive level. In contrast, the catfish GnRH and rat TRH receptors, which have cytoplasmic carboxyl-terminal tails, displayed similar levels of constitutive agonist-independent internalization but underwent robust agonist-dependent internalization, as did chimeras of the mammalian type I GnRH receptor with the cytoplasmic carboxyl-terminal tails of the catfish GnRH receptor or the rat TRH receptor. When the carboxyl-terminal Tyr325 and Leu328 residues of the mammalian type I GnRH receptor were replaced with alanines, these two mutant receptors underwent significantly impaired internalization, suggesting a function for the Tyr-X-X-Leu sequence in mediating the constitutive agonist-independent internalization of mammalian type I GnRH receptors. These findings provide further support for the underlying notion that the absence of the cytoplasmic carboxyl-terminal tail of the mammalian type I GnRH receptors has been selected for during evolution to prevent rapid receptor desensitization and internalization to allow protracted GnRH signaling in mammals.

scholarly journals Selectivity Landscape of 100 Therapeutically Relevant GPCR Profiled by an Effector Translocation-Based BRET Platform

2020 ◽  
Author(s):  
Charlotte Avet ◽  
Arturo Mancini ◽  
Billy Breton ◽  
Christian Le Gouill ◽  
Alexander S. Hauser ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Drug Discovery ◽  
Signaling Pathways ◽  
G Protein ◽  
G Protein Coupled Receptors ◽  
Systems Pharmacology ◽  
New Knowledge ◽  
Translocation Assay ◽  
Multiple Signaling ◽  
G Protein Coupled

SUMMARYThe ability of individual G protein-coupled receptors (GPCR) to engage multiple signaling pathways opens opportunities for the development of better drugs. This requires new knowledge and tools to determine the G protein subtypes and βarrestins engaged by a given receptor. Here, we used a new BRET-based effector membrane translocation assay (EMTA) that monitors activation of each Gα protein through the recruitment of selective G protein effectors and βarrestins to the plasma membrane. Profiling of 100 therapeutically relevant GPCR revealed a great diversity of coupling profiles with some receptors displaying exquisite selectivity, whereas others promiscuitely engage all four G protein families. Comparison with existing datasets points to commonalities but also to critical differences between studies. Combining a biosensor subset allowed detecting activity of nearly all GPCR thus providing a new tool for safety screens and systems pharmacology. Overall, this work describes unique resources for studying GPCR function and drug discovery.

scholarly journals Fungal G-Protein-Coupled Receptors: A Promising Mediator of the Impact of Extracellular Signals on Biosynthesis of Ochratoxin A

2021 ◽  
Vol 12 ◽  
Author(s):  
Jing Gao ◽  
Xinge Xu ◽  
Kunlun Huang ◽  
Zhihong Liang
Keyword(s):  
G Protein ◽  
Ochratoxin A ◽  
G Protein Coupled Receptors ◽  
Aspergillus Ochraceus ◽  
Transmembrane Receptors ◽  
Environmental Signals ◽  
Extracellular Signals ◽  
Fungal Biology ◽  
The Impact ◽  
G Protein Coupled

G-protein-coupled receptors (GPCRs) are transmembrane receptors involved in transducing signals from the external environment inside the cell, which enables fungi to coordinate cell transport, metabolism, and growth to promote their survival, reproduction, and virulence. There are 14 classes of GPCRs in fungi involved in sensing various ligands. In this paper, the synthesis of mycotoxins that are GPCR-mediated is discussed with respect to ligands, environmental stimuli, and intra-/interspecific communication. Despite their apparent importance in fungal biology, very little is known about the role of ochratoxin A (OTA) biosynthesis by Aspergillus ochraceus and the ligands that are involved. Fortunately, increasing evidence shows that the GPCR that involves the AF/ST (sterigmatocystin) pathway in fungi belongs to the same genus. Therefore, we speculate that GPCRs play an important role in a variety of environmental signals and downstream pathways in OTA biosynthesis. The verification of this inference will result in a more controllable GPCR target for control of fungal contamination in the future.

Targeting of cytosolic phospholipase A2 to plasma membrane inhibits its activation by G-protein coupled receptors

Lipids ◽  
1999 ◽  
Vol 34 (S1) ◽  
pp. S67-S67
Author(s):  
Elsa Klapisz ◽  
Mouloud Ziari ◽  
Kamen Koumanov ◽  
Dominique Wendum ◽  
Corinne Brachet ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Phospholipase A2 ◽  
G Protein ◽  
Cytosolic Phospholipase A2 ◽  
G Protein Coupled Receptors ◽  
Cytosolic Phospholipase ◽  
G Protein Coupled

Glucagon counteracts interleukin-6-dependent gene expression by redundant action of Epac and PKA

2011 ◽  
Vol 392 (12) ◽  
pp. 1123-1134 ◽  
Author(s):  
Christina Khouri ◽  
Anna Dittrich ◽  
Sara Dutton Sackett ◽  
Bernd Denecke ◽  
Christian Trautwein ◽  
...  
Keyword(s):  
Gene Expression ◽  
G Protein ◽  
Acute Phase ◽  
Interleukin 6 ◽  
Biological Response ◽  
Underlying Mechanism ◽  
G Protein Coupled Receptors ◽  
Counterregulatory Hormones ◽  
The Impact ◽  
G Protein Coupled

AbstractInflammation is the biological response to injurious stimuli. In the initial phase of the inflammatory process, interleukin-6 (IL-6) is the main inducer of acute phase protein expression in the liver. A prolonged acute phase response is characterised by a disturbed glucose homeostasis and elevated levels of IL-6, insulin, and counterregulatory hormones such as glucagon. Several studies deal with the impact of IL-6 on glucagon-dependent gene expression. In contrast, only very little is known about the influence of G-protein-coupled receptors on IL-6 signalling. Therefore, the aim of this study is to elucidate the regulation of IL-6-induced gene expression by glucagon. We could reveal a novel mechanism of negative regulation of IL-6-induced MAP kinase activation by glucagon in primary murine hepatocytes. IL-6-dependent induction of the ERK-dependent target geneTfpi2, coding for a Kunitz-type serine protease inhibitor, was strongly down-regulated by glucagon treatment. Studying the underlying mechanism revealed a redundant action of the signalling molecules exchange protein activated by cyclic AMP (Epac) and protein kinase A. The metabolic hormone glucagon interferes in IL-6-induced gene expression. This observation is indicative for a regulatory role of G-protein-coupled receptors in the IL-6-dependent inflammatory response.

scholarly journals Identification of G Protein α Subunit-Palmitoylating Enzyme

2008 ◽  
Vol 29 (2) ◽  
pp. 435-447 ◽  
Author(s):  
Ryouhei Tsutsumi ◽  
Yuko Fukata ◽  
Jun Noritake ◽  
Tsuyoshi Iwanaga ◽  
Franck Perez ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Plasma Membrane ◽  
G Protein ◽  
Adrenergic Receptor ◽  
Fluorescence Recovery After Photobleaching ◽  
G Protein Coupled Receptors ◽  
Α Subunit ◽  
Cytoplasmic Face ◽  
G Protein Α Subunit ◽  
G Protein Coupled

ABSTRACT The heterotrimeric G protein α subunit (Gα) is targeted to the cytoplasmic face of the plasma membrane through reversible lipid palmitoylation and relays signals from G-protein-coupled receptors (GPCRs) to its effectors. By screening 23 DHHC motif (Asp-His-His-Cys) palmitoyl acyl-transferases, we identified DHHC3 and DHHC7 as Gα palmitoylating enzymes. DHHC3 and DHHC7 robustly palmitoylated Gαq, Gαs, and Gαi2 in HEK293T cells. Knockdown of DHHC3 and DHHC7 decreased Gαq/11 palmitoylation and relocalized it from the plasma membrane into the cytoplasm. Photoconversion analysis revealed that Gαq rapidly shuttles between the plasma membrane and the Golgi apparatus, where DHHC3 specifically localizes. Fluorescence recovery after photobleaching studies showed that DHHC3 and DHHC7 are necessary for this continuous Gαq shuttling. Furthermore, DHHC3 and DHHC7 knockdown blocked the α1A-adrenergic receptor/Gαq/11-mediated signaling pathway. Together, our findings revealed that DHHC3 and DHHC7 regulate GPCR-mediated signal transduction by controlling Gα localization to the plasma membrane.

Progress in demystification of adhesion G protein-coupled receptors

2013 ◽  
Vol 394 (8) ◽  
pp. 937-950 ◽  
Author(s):  
Ines Liebscher ◽  
Torsten Schöneberg ◽  
Simone Prömel
Keyword(s):  
G Protein ◽  
Usher Syndrome ◽  
G Protein Coupled Receptors ◽  
Dual Function ◽  
Cell Matrix ◽  
Proteolytic Site ◽  
Functional Features ◽  
Cell Matrix Interactions ◽  
Adhesion Gpcr ◽  
G Protein Coupled

Abstract Adhesion G protein-coupled receptors (aGPCR) form the second largest class of GPCR. They are phylogenetically old and have been highly conserved during evolution. Mutations in representatives of this class are associated with severe diseases such as Usher Syndrome, a combined congenital deaf-blindness, or bifrontal parietal polymicrogyria. The main characteristics of aGPCR are their enormous size and the complexity of their N termini. They contain a highly conserved GPCR proteolytic site (GPS) and several functional domains that have been implicated in cell-cell and cell-matrix interactions. Adhesion GPCR have been proposed to serve a dual function as adhesion molecules and as classical receptors. However, until recently there was no proof that aGPCR indeed couple to G proteins or even function as classical receptors. In this review, we have summarized and discussed recent evidence that aGPCR present many functional features of classical GPCR, including multiple G protein-coupling abilities, G protein-independent signaling and oligomerization, but also specific signaling properties only found in aGPCR.

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