The adhesion <scp>GPCR</scp> Adgrg6 (Gpr126): Insights from the zebrafish model

Baxendale, Sarah; Asad, Anzar; Shahidan, Nahal O; Wiggin, Giselle R.; Whitfield, Tanya T.

doi:10.1002/dvg.23417

Cited by 10 publications

(11 citation statements)

References 107 publications

(207 reference statements)

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“…The Gpr126-deficient mice show an embryonic lethal phenotype mainly due to cardiac abnormality [103]. In addition, Gpr126 deficiency also leads to multiple defects in peripheral nerves [104], inner ear (in zebrafish) [105], placental development [106], and lack of myelination in the peripheral nervous system (PNS) [107]. More recent studies in cell typespecific Gpr126 knock out animals further indicated a role for GPR126 in the regulation of body length and bone mass as well as the maintenance of spinal alignment [108,109].…”

Section: Adgrg6/gpr126mentioning

confidence: 99%

Ligands and Beyond: Mechanosensitive Adhesion GPCRs

Lin

Chen

et al. 2022

Pharmaceuticals

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Cells respond to diverse types of mechanical stimuli using a wide range of plasma membrane-associated mechanosensitive receptors to convert extracellular mechanical cues into intracellular signaling. G protein-coupled receptors (GPCRs) represent the largest cell surface protein superfamily that function as versatile sensors for a broad spectrum of bio/chemical messages. In recent years, accumulating evidence has shown that GPCRs can also engage in mechano-transduction. According to the GRAFS classification system of GPCRs, adhesion GPCRs (aGPCRs) constitute the second largest GPCR subfamily with a unique modular protein architecture and post-translational modification that are well adapted for mechanosensory functions. Here, we present a critical review of current evidence on mechanosensitive aGPCRs.

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Section: Adgrg6/gpr126mentioning

confidence: 99%

Ligands and Beyond: Mechanosensitive Adhesion GPCRs

Lin

Chen

et al. 2022

Pharmaceuticals

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“…Additional activation can be achieved through the receptor’s N-terminal ligands collagen IV ( Paavola et al, 2014 ), prion protein PrP C ( Küffer et al, 2016 ), and laminin 211 ( Petersen et al, 2015 ). Yet, none of these agonists is specific for GPR126, and ECM proteins lack characteristics of a classic receptor agonist as they are long-lived, stable molecules with essentially no diffusivity ( Bassilana et al, 2019 ; Baxendale et al, 2021 ). Thus, it is unclear how the interaction between aGPCR and the ECM can be interpreted as a specific signal to modulate receptor activity levels.…”

Section: Introductionmentioning

confidence: 99%

The N Terminus of Adhesion G Protein–Coupled Receptor GPR126/ADGRG6 as Allosteric Force Integrator

Mitgau¹,

Franke

Schinner

et al. 2022

Front. Cell Dev. Biol.

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The adhesion G protein–coupled receptor (aGPCR) GPR126/ADGRG6 plays an important role in several physiological functions, such as myelination or peripheral nerve repair. This renders the receptor an attractive pharmacological target. GPR126 is a mechano-sensor that translates the binding of extracellular matrix (ECM) molecules to its N terminus into a metabotropic intracellular signal. To date, the structural requirements and the character of the forces needed for this ECM-mediated receptor activation are largely unknown. In this study, we provide this information by combining classic second-messenger detection with single-cell atomic force microscopy. We established a monoclonal antibody targeting the N terminus to stimulate GPR126 and compared it to the activation through its known ECM ligands, collagen IV and laminin 211. As each ligand uses a distinct mode of action, the N terminus can be regarded as an allosteric module that can fine-tune receptor activation in a context-specific manner.

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“…Furthermore, GPR126 has been reported to have critical roles in the normal development of diverse organs and tissues, including Schwann cells and peripheral nervous system myelination, bone, inner ear, and placenta (Baxendale et al, 2021). Of note, human GPR126 mutations are linked to several nonneurological diseases, such as adolescent idiopathic scoliosis (Kou et al, 2013), arthrogryposis multiplex congenital (Ravenscroft et al, 2015), and carcinogenesis (An et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

Dual role of brain endothelial Gpr126 in blood-brain barrier development and ischemic stroke

Kakogiannos

Scalise

Martini

et al. 2022

Preprint

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The blood–brain barrier (BBB) acquires unique properties for regulation of the neuronal function during development. The genesis of the BBB coupled with angiogenesis is orchestrated by the Wnt/β–catenin signaling pathway. Aside from the importance of Wnt/β–catenin signaling, the molecular mechanisms that regulate these processes are poorly understood. Here, we identify the brain endothelial adhesion G–protein–coupled receptor Gpr126 as a novel target gene of Wnt/β–catenin signaling that is required for postnatal BBB development, and its expression is detrimental for ischemic stroke in adults. We show that Gpr126 expression is high in mouse brain endothelium during BBB formation, but decreases in the adult. Inactivation of Gpr126 in postnatal endothelial cells results in vessel enlargement and impairs acquisition of the BBB characteristics, such as increased neurovascular permeability, and reduced basement membrane protein deposition and pericyte coverage. Mechanistically, Gpr126 is required during developmental angiogenesis to promote endothelial cell migration, acting via an interaction between Lrp1 and β1–integrin, which couples vessel morphogenesis to BBB formation. Interestingly, in adult mice with an established BBB, the lack of Gpr126 expression in acute ischemic stroke is protective and coupled with reduced microglia activation, which contributes to an improved neurological outcome. These data identify Gpr126 as a promising therapeutic target to treat ischemic stroke.

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The adhesion GPCR Adgrg6 (Gpr126): Insights from the zebrafish model

Cited by 10 publications

References 107 publications

Ligands and Beyond: Mechanosensitive Adhesion GPCRs

Ligands and Beyond: Mechanosensitive Adhesion GPCRs

The N Terminus of Adhesion G Protein–Coupled Receptor GPR126/ADGRG6 as Allosteric Force Integrator

Dual role of brain endothelial Gpr126 in blood-brain barrier development and ischemic stroke

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