Adhesion G protein–coupled receptors—Candidate metabotropic mechanosensors and novel drug targets

Langenhan, Tobias

doi:10.1111/bcpt.13223

Cited by 51 publications

(54 citation statements)

References 145 publications

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“…The current evidence supports two fundamental modes of AGPCR modulation: orthosteric agonism (i.e. tethered-peptide agonism), in which NTF / CTF dissociation is required, and allosteric regulation, which has also been termed the tunable model and does not require receptor subunit dissociation (21,30,31,33,35). Both fundamental activation modes are supported through several lines of evidence and it is likely that individual AGPCRs can be activated in both manners.…”

Section: Adhesion Gpcr Activation Mechanismssupporting

confidence: 58%

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Mechanisms of adhesion G protein–coupled receptor activation

Vizurraga

Adhikari

Yeung

et al. 2020

Journal of Biological Chemistry

114

141

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Adhesion G protein coupled receptors (AGPCRs) are a thirty-three-member subfamily of Class B GPCRs that control a wide array of physiological processes and are implicated in disease. AGPCRs uniquely contain large, self-proteolyzing extracellular regions that range from hundreds to thousands of residues in length. AGPCR autoproteolysis occurs within the extracellular GPCR Autoproteolysis-Inducing (GAIN) domain that is proximal to the N-terminus of the G protein-coupling seven transmembrane spanning (7TM) bundle. GAIN domain-mediated self-cleavage is constitutive and produces two-fragment holoreceptors that remain bound at the cell surface. It has been of recent interest to understand how AGPCRs are activated in relation to their two-fragment topologies. Dissociation of the AGPCR fragments stimulates G protein signaling through the action of the tethered-peptide-agonist stalk that is occluded within the GAIN domain in the holoreceptor form. AGPCRs can also signal independently of fragment dissociation, and a few receptors possess GAIN domains incapable of self-proteolysis. This has resulted in complex theories as to how these receptors are activated in vivo, complicating pharmacological advances. Currently there is no existing structure of an activated AGPCR to support any of the theories. Further confounding AGPCR research is that many of the receptors remain orphans and lack identified activating ligands. In this review, we provide a detailed layout of the current theorized modes of AGPCR activation with discussion of potential parallels to mechanisms used by other GPCR classes. We provide a classification means for the ligands that have been identified and discuss how these ligands may activate AGPCRs in physiological-contexts.

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Section: Adhesion Gpcr Activation Mechanismssupporting

confidence: 58%

“…An understanding of the ways that AGPCRs become activated is emerging. There has been a broad and imaginative variety of proposed AGPCR activation schemes (10,(29)(30)(31)(32)(33)(34). The current evidence supports two fundamental modes of AGPCR modulation: orthosteric agonism (i.e.…”

Section: Adhesion Gpcr Activation Mechanismsmentioning

confidence: 61%

Mechanisms of adhesion G protein–coupled receptor activation

Vizurraga

Adhikari

Yeung

et al. 2020

Journal of Biological Chemistry

114

141

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“…These findings are important amendments to the current knowledge of the biology of GPR125. No ligands have yet been described for GPR125, and it, therefore, still remains an orphan, like most aGPCRs . Moreover, its cleavage status is not known and based on its atypical GPS‐motif (SLS) and not the usual (HLS/HLT), it is possibly not cleaved via an autoproteolytic process.…”

Section: Discussionmentioning

confidence: 99%

Arrestin‐independent constitutive endocytosis of GPR125/ADGRA3

Spieß

Bagger

Torz

et al. 2019

Annals of the New York Academy of Sciences

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The orphan receptor GPR125 (ADGRA3) belongs to subgroup III of the adhesion G protein−coupled receptor (aGPCR) family. aGPCRs, also known as class B2 GPCRs, share basic structural and functional properties with other GPCRs. Many of them couple to G proteins and activate G protein−dependent and −independent signaling pathways, but little is known about aGPCR internalization and β-arrestin recruitment. GPR125 was originally described as a spermatogonial stem cell marker and studied for its role in Wnt signaling and cell polarity. Here, using cell-based assays and confocal microscopy, we show that GPR125 is expressed on the cell surface and undergoes constitutive endocytosis in a β-arrestin−independent, but clathrin-dependent manner, as indicated by colocalization with transferrin receptor 1, an early endosome marker. These data support that the constitutive internalization of GPR125 contributes to its biological functions by controlling receptor surface expression and accessibility for ligands. Our study sheds light on a new property of aGPCRs, namely internalization; a property described to be important for signal propagation, signal termination, and desensitization of class A (rhodopsin-like) and B1 (VIP/secretin) GPCRs.

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“…The AC consists of the plasma membrane and the underlying actin cytoskeleton, linked together by a rich pool of transmembrane and adaptor proteins [10]. The structure and biomechanics of the AC are tightly intertwined [11,12] and they in turn influence the functionality of molecular mechanosensors, such as Piezo mechanosensitive ion channels [13,14] or G-protein coupled receptors [15,16]. These are incorporated into the plasma membrane and directly convert mechanical stimuli into downstream biochemical signals.…”

Section: Introductionmentioning

confidence: 99%

Elasticity spectra as a tool to investigate actin cortex mechanics

et al. 2020

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Background The mechanical properties of single living cells have proven to be a powerful marker of the cell physiological state. The use of nanoindentation-based single cell force spectroscopy provided a wealth of information on the elasticity of cells, which is still largely to be exploited. The simplest model to describe cell mechanics is to treat them as a homogeneous elastic material and describe it in terms of the Young’s modulus. Beside its simplicity, this approach proved to be extremely informative, allowing to assess the potential of this physical indicator towards high throughput phenotyping in diagnostic and prognostic applications. Results Here we propose an extension of this analysis to explicitly account for the properties of the actin cortex. We present a method, the Elasticity Spectra, to calculate the apparent stiffness of the cell as a function of the indentation depth and we suggest a simple phenomenological approach to measure the thickness and stiffness of the actin cortex, in addition to the standard Young’s modulus. Conclusions The Elasticity Spectra approach is tested and validated on a set of cells treated with cytoskeleton-affecting drugs, showing the potential to extend the current representation of cell mechanics, without introducing a detailed and complex description of the intracellular structure.

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Adhesion G protein–coupled receptors—Candidate metabotropic mechanosensors and novel drug targets

Cited by 51 publications

References 145 publications

Mechanisms of adhesion G protein–coupled receptor activation

Mechanisms of adhesion G protein–coupled receptor activation

Arrestin‐independent constitutive endocytosis of GPR125/ADGRA3

Elasticity spectra as a tool to investigate actin cortex mechanics

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