Adhesion G Protein–Coupled Receptors: From In Vitro Pharmacology to In Vivo Mechanisms

Monk, Kelly R.; Hamann, Jörg; Langenhan, Tobias; Nijmeijer, Saskia; Schöneberg, Torsten; Liebscher, Ines

doi:10.1124/mol.115.098749

Cited by 52 publications

(47 citation statements)

References 67 publications

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“…Intriguingly, myelin defects in gpr126 mutants could be rescued by cAMP elevation, suggestive of G s coupling. These studies are discussed in more detail in Monk et al (2015). At the Lorentz Center workshop, more recent advances in understanding how Gpr126 controls Schwann cell development and myelination were presented.…”

Section: Animal Models To Discover and Validate Molecular Conceptsmentioning

confidence: 99%

“…Several findings, obtained through phenotypic analyses of null or hypomorphic mutants of aGPCR genes in animal models, have established that these receptors function during developmentally dynamic periods of organogenesis and are involved in cell differentiation, migration, and polarity, similar to Frizzled-type GPCRs (Schulte, 2010;Dijksterhuis et al, 2014). However, whether aGPCRs also function in postmitotic tissue, which signals they read out, and how they transduce these into intracellular messages has only recently begun to unfold (see also Monk et al, 2015). Among others, two aGPCR homologs, Gpr126 (ADGRG6) and Latrophilin (ADGRGL1-3), have served as model receptors to dissect aGPCR signals.…”

Section: Animal Models To Discover and Validate Molecular Conceptsmentioning

confidence: 99%

“…(B) The aGPCR Latrophilin/Cirl is present in mechanosensory neurons of Drosophila, where it regulates their sensitivity toward mechanical stimulation and maintains a physiological signal-to-noise ratio. Loss of Latrophilin/Cirl results in numbness, amblyacousia, and proprioception deficits (Monk et al, 2015;Scholz et al, 2015).…”

Section: Animal Models To Discover and Validate Molecular Conceptsmentioning

confidence: 99%

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Model Organisms in G Protein–Coupled Receptor Research

et al. 2015

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The study of G protein-coupled receptors (GPCRs) has benefited greatly from experimental approaches that interrogate their functions in controlled, artificial environments. Working in vitro, GPCR receptorologists discovered the basic biologic mechanisms by which GPCRs operate, including their eponymous capacity to couple to G proteins; their molecular makeup, including the famed serpentine transmembrane unit; and ultimately, their three-dimensional structure. Although the insights gained from working outside the native environments of GPCRs have allowed for the collection of low-noise data, such approaches cannot directly address a receptor's native (in vivo) functions. An in vivo approach can complement the rigor of in vitro approaches: as studied in model organisms, it imposes physiologic constraints on receptor action and thus allows investigators to deduce the most salient features of receptor function. Here, we briefly discuss specific examples in which model organisms have successfully contributed to the elucidation of signals controlled through GPCRs and other surface receptor systems. We list recent examples that have served either in the initial discovery of GPCR signaling concepts or in their fuller definition. Furthermore, we selectively highlight experimental advantages, shortcomings, and tools of each model organism.

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Section: Animal Models To Discover and Validate Molecular Conceptsmentioning

confidence: 99%

Section: Animal Models To Discover and Validate Molecular Conceptsmentioning

confidence: 99%

Section: Animal Models To Discover and Validate Molecular Conceptsmentioning

confidence: 99%

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Model Organisms in G Protein–Coupled Receptor Research

et al. 2015

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“…Adhesion GPCRs have a highly conserved GPCR proteolysis site (GPS), which is cleaved by an intramolecular autocatalytic reaction (35). The proteinase-activated receptors (PARs) are a subfamily of GPCRs activated by serine proteases (36), although a metalloproteinase is also involved in the regulated proteolysis of PAR1 (35).…”

Section: Galnac-t2 Fine-tunes ␤ 1 Ar Ectodomain Cleavagementioning

confidence: 99%

Site-specific O-Glycosylation by Polypeptide N-Acetylgalactosaminyltransferase 2 (GalNAc-transferase T2) Co-regulates β1-Adrenergic Receptor N-terminal Cleavage

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Tuhkanen

Khan

et al. 2017

Journal of Biological Chemistry

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Edited by F. Anne StephensonThe ␤ 1 -adrenergic receptor (␤ 1 AR) is a G protein-coupled receptor (GPCR) and the predominant adrenergic receptor subtype in the heart, where it mediates cardiac contractility and the force of contraction. Although it is the most important target for ␤-adrenergic antagonists, such as ␤-blockers, relatively little is yet known about its regulation. We have shown previously that ␤ 1 AR undergoes constitutive and regulated N-terminal cleavage participating in receptor down-regulation and, moreover, that the receptor is modified by O-glycosylation. Here we demonstrate that the polypeptide GalNAc-transferase 2 (GalNAc-T2) specifically O-glycosylates ␤ 1 AR at five residues in the extracellular N terminus, including the Ser-49 residue at the location of the common S49G single-nucleotide polymorphism. Using in vitro O-glycosylation and proteolytic cleavage assays, a cell line deficient in O-glycosylation, GalNAc-T-edited cell line model systems, and a GalNAc-T2 knock-out rat model, we show that GalNAc-T2 co-regulates the metalloproteinase-mediated limited proteolysis of ␤ 1 AR. Furthermore, we demonstrate that impaired O-glycosylation and enhanced proteolysis lead to attenuated receptor signaling, because the maximal response elicited by the ␤AR agonist isoproterenol and its potency in a cAMP accumulation assay were decreased in HEK293 cells lacking GalNAc-T2. Our findings reveal, for the first time, a GPCR as a target for co-regulatory functions of site-specific O-glycosylation mediated by a unique GalNAc-T isoform. The results provide a new level of ␤ 1 AR regulation that may open up possibilities for new therapeutic strategies for cardiovascular diseases. ␤-Adrenergic receptors (␤ARs)4 are G protein-coupled receptors (GPCRs) that activate intracellular signaling pathways mainly via the stimulatory G s protein after binding of agonists such as adrenaline and noradrenaline (1, 2). The ␤ARs exist as three subtypes, ␤ 1 , ␤ 2 , and ␤ 3 , and the former two are important in the regulation of the excitation-contraction coupling of the myocardium. The ␤ 1 AR is the predominant ␤AR subtype expressed in the heart and the main mediator of the endogenous catecholamine-stimulated positive chronotropy and inotropy (1, 2). Thus, it is the most important target receptor for ␤-adrenergic antagonists, also called ␤-blockers, which are widely used in the treatment of cardiac diseases, such as chronic heart failure, coronary artery disease, arrhythmias, and hypertension. However, these therapeutic agents have limited effectiveness in some patients and also exert adverse effects. Consequently, there is a growing need to better understand the underlying mechanisms in cardiac function and disease to develop alternative and more individualized treatment options that can improve clinical outcomes.During chronic heart failure, a persistent compensatory increase of catecholamines causes ␤ 1 AR desensitization and down-regulation. The density of ␤ 1 ARs at the plasma membrane is reduced by 50%, whereas that of ␤...

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“…interpretation of GPCR crystal structures, importance of ligand residence time, GPCR multimers, the promise of biased signaling in vivo, spatial and temporal aspects of GPCR signaling, studying GPCR signaling with resonance energy transfer biosensors in vivo, model organisms in GPCR research, and a novel class of adhesion GPCRs and GPCR signaling networks from a systems biology perspective Langenhan et al, 2015;Lohse and Hofmann, 2015;Luttrell et al, 2015;Monk et al, 2015;Piscitelli et al, 2015;Roth et al, 2015;van Unen et al, 2015;Vischer et al, 2015). Scientists with expertise in in vitro and in vivo GPCR studies participated in the different reviews, thus bridging these fields.…”

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confidence: 99%

Exploring the Biology of G Protein–Coupled Receptors from In Vitro to In Vivo

et al. 2015

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In August 2014, an international group of researchers gathered for 5 days at the Lorentz Center in Leiden, The Netherlands, to explore the technical and conceptual issues associated with the analysis of G protein-coupled receptor functions utilizing information from crystal structure models to the use of model organisms. This collection of review articles evolved from the 5-day meeting, with brief presentations and structured discussion periods that were designed to identify key questions remaining in understanding G protein-coupled receptor function and to propose novel strategies by integrating scientific disciplines to guide future research.

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Adhesion G Protein–Coupled Receptors: From In Vitro Pharmacology to In Vivo Mechanisms

Cited by 52 publications

References 67 publications

Model Organisms in G Protein–Coupled Receptor Research

Model Organisms in G Protein–Coupled Receptor Research

Site-specific O-Glycosylation by Polypeptide N-Acetylgalactosaminyltransferase 2 (GalNAc-transferase T2) Co-regulates β1-Adrenergic Receptor N-terminal Cleavage

Exploring the Biology of G Protein–Coupled Receptors from In Vitro to In Vivo

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