The expanding functional roles and signaling mechanisms of adhesion G protein–coupled receptors

Morgan, Rory K.; Anderson, Garret R.; Araç, Demet; Aust, Gabriela; Balenga, Nariman; Boucard, Antony A.; Bridges, James P.; Engel, Felix B.; Formstone, Caroline J.; Glitsch, Maike D.; Gray, Ryan S.; Hall, Randy A.; Hsiao, Cheng-Chih; Kim, Hee Yong; Knierim, Alexander Bernd; Kusuluri, Deva Krupakar; Leon, Katherine; Liebscher, Ines; Piao, Xiangshu; Prömel, Simone; Scholz, Nicole; Srivastava, Swati; Thor, Doreen; Tolias, Kimberley F.; Ushkaryov, Yuri A.; Vallon, Mario; Meir, Erwin G. Van; Vanhollebeke, Benoît; Wolfrum, Uwe; Wright, Kevin M.; Monk, Kelly R.; Mogha, Amit

doi:10.1111/nyas.14094

Cited by 18 publications

(18 citation statements)

References 112 publications

(163 reference statements)

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“…Adhesion-GPCRs characteristically contain large extracellular sequences with multiple potential ligand-binding domains and a canonical GAIN domain that is coupled to the 7transmembrane region module characteristic of GPCRs (reviewed in Vizurraga et al, 2020;Morgan et al, 2019;Folts et al, 2019;Purcell and Hall, 2018). Most adhesion-GPCRs additionally have a long cytoplasmic region.…”

Section: Introductionmentioning

confidence: 99%

Latrophilin GPCR signaling mediates synapse formation

Sando

Südhof

2021

eLife

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Neural circuit assembly in the brain requires precise establishment of synaptic connections, but the mechanisms of synapse assembly remain incompletely understood. Latrophilins are postsynaptic adhesion-GPCRs that engage in trans-synaptic complexes with presynaptic teneurins and FLRTs. In mouse CA1-region neurons, Latrophilin-2 and Latrophilin-3 are essential for formation of entorhinal-cortex-derived and Schaffer-collateral-derived synapses, respectively. However, it is unknown whether latrophilins function as GPCRs in synapse formation. Here, we show that Latrophilin-2 and Latrophilin-3 exhibit constitutive GPCR activity that increases cAMP levels, which was blocked by a mutation interfering with G-protein and arrestin interactions of GPCRs. The same mutation impaired the ability of Latrophilin-2 and Latrophilin-3 to rescue the synapse-loss phenotype in Latrophilin-2 and Latrophilin-3 knockout neurons in vivo. Our results suggest that Latrophilin-2 and Latrophilin-3 require GPCR signaling in synapse formation, indicating that latrophilins promote synapse formation in the hippocampus by activating a classical GPCR-signaling pathway.

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Section: Introductionmentioning

confidence: 99%

Latrophilin GPCR signaling mediates synapse formation

Sando

Südhof

2021

eLife

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“…Adhesion-GPCRs characteristically contain large extracellular sequences with multiple potential ligand-binding domains and a canonical GAIN domain that is coupled to the 7-transmembrane region module characteristic of GPCRs (reviewed in Vizurraga et al, 2020; Morgan et al, 2019; Folts et al, 2019; Purcell and Hall, 2018). Most adhesion-GPCRs additionally have a long cytoplasmic region.…”

Section: Introductionmentioning

confidence: 99%

Latrophilin GPCR Signaling Mediates Synapse Formation

Sando

Südhof

2021

Preprint

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Neural circuit assembly in the brain requires precise establishment of synaptic connections, but the mechanisms of synapse assembly remain incompletely understood. Latrophilins are postsynaptic adhesion-GPCRs that engage in trans-synaptic complexes with presynaptic teneurins and FLRTs. In CA1-region neurons, Latrophilin-2 and Latrophilin-3 are essential for formation of entorhinal-cortex-derived and Schaffer-collateral-derived synapses, respectively. However, it is unknown whether latrophilins function as GPCRs in synapse formation. Here, we show that Latrophilin-2 and Latrophilin-3 exhibit constitutive GPCR activity that increases cAMP levels, which was blocked by a mutation interfering with G-protein and arrestin interactions of GPCRs. The same mutation impaired the ability of Latrophilin-2 and Latrophilin-3 to rescue the synapse-loss phenotype in Latrophilin-2 and Latrophilin-3 knockout neurons in vivo. Our results suggest that Latrophilin-2 and Latrophilin-3 require GPCR signaling in synapse formation, indicating that latrophilins promote synapse formation in the hippocampus by activating a classical GPCR-signaling pathway.

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“…This in combination with recent advances in our understanding of GPCR structures has formed a strong foundation for rational drug design to target this largest superfamily of surface receptors 4,5 . Recent genomic and model organism studies have revealed the versatile roles that the adhesion GPCRs (aGPCRs), the second-largest family of GPCRs, play in endocrine, nervous and immune systems 6 . aGPCRs have structural differences with other classes of GPCRs, namely autoproteolysis at a GPCR proteolysis site (GPS) and formation of a two-segmented receptor with a large N-terminal fragment (NTF) and a C-terminal fragment (CTF).…”

Section: Introductionmentioning

confidence: 99%

Conserved residues in the extracellular loop 2 regulateStachel-mediated activation of ADGRG2

Gad

Azimzadeh

Balenga

2021

Preprint

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Cleavage and dissociation of a large N-terminal fragment and the consequent unmasking of a short sequence (Stachel) remaining on the N-terminus have been proposed as mechanisms of activation of some members of the adhesion G protein-coupled receptor (aGPCR) family. However, the identity of residues that play a role in the activation of aGPCRs by the cognate Stachel remains largely unknown. Protein sequence alignments revealed a conserved stretch of residues in the extracellular loop 2 (ECL2) of all 33 members of the aGPCR family. ADGRG2, an orphan aGPCR, plays a major role in male fertility, Ewing sarcoma cell proliferation, and parathyroid cell function. We used ADGRG2 as a model aGPCR and generated mutants of the conserved residues in the ECL2 via site-directed mutagenesis. We show that tryptophan and isoleucine in the ECL2 are required for receptor stability and surface expression in the HEK293 cells. By adjusting the receptor surface expression levels, we show that the ECL2 mutation ablates the Stachel-mediated activation of multiple signaling pathways of ADGRG2. This study provides a novel understanding of the role of the ECL2 in Stachel-mediated signaling and degradation of ADGRG2, which may lay the foundation for the rational design of therapeutics to target aGPCRs.

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The expanding functional roles and signaling mechanisms of adhesion G protein–coupled receptors

Cited by 18 publications

References 112 publications

Latrophilin GPCR signaling mediates synapse formation

Latrophilin GPCR signaling mediates synapse formation

Latrophilin GPCR Signaling Mediates Synapse Formation

Conserved residues in the extracellular loop 2 regulateStachel-mediated activation of ADGRG2

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