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Downstream signalling of the disease-associated mutations on GPR56/ADGRG1
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Basic Clin Pharma Tox - 2023 - Cevhero lu - Downstream signalling of the disease‐associated mutations on GPR56 ADGRG1.pdf
Date
2023-01-01
Author
CEVHEROĞLU, ORKUN
Demir, Nil
Kesici, Mehmet Seçkin
Özçubukçu, Salih
Son, Çağdaş Devrim
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GPR56/ADGRG1 is an adhesion G protein-coupled receptor (GPCR) and mutations on this receptor cause cortical malformation due to the over-migration of neural progenitor cells on brain surface. At pial surface, GPR56 interacts with collagen III, induces Rho-dependent activation through Gα12/13 and inhibits the neuronal migration. In human glioma cells, GPR56 inhibits cell migration through Gαq/11-dependent Rho pathway. GPR56-tetraspanin complex is known to couple Gαq/11. GPR56 is an aGPCR that couples with various G proteins and signals through different downstream pathways. In this study, bilateral frontoparietal polymicrogyria (BFPP) mutants disrupting GPR56 function but remaining to be expressed on plasma membrane were used to study receptor signalling through Gα12, Gα13 and Gα11 with BRET biosensors. GPR56 showed coupling with all three G proteins and activated heterotrimeric G protein signalling upon stimulation with Stachel peptide. However, BFPP mutants showed different signalling defects for each G protein indicative of distinct activation and signalling properties of GPR56 for Gα12, Gα13 or Gα11. β-arrestin recruitment was also investigated following the activation of GPR56 with Stachel peptide using BRET biosensors. N-terminally truncated GPR56 showed enhanced β-arrestin recruitment; however, neither wild-type receptor nor BFPP mutants gave any measurable recruitment upon Stachel stimulation, pointing different activation mechanisms for β-arrestin involvement.
Subject Keywords
ADGRG1
,
adhesion GPCR
,
bilateral frontoparietal polymicrogyria (BFPP)
,
biosensor
,
G protein
,
GPCR
,
GPR56
,
β-arrestin
URI
https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85153478794&origin=inward
https://hdl.handle.net/11511/103005
Journal
Basic and Clinical Pharmacology and Toxicology
DOI
https://doi.org/10.1111/bcpt.13873
Collections
Department of Chemistry, Article
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BibTeX
O. CEVHEROĞLU, N. Demir, M. S. Kesici, S. Özçubukçu, and Ç. D. Son, “Downstream signalling of the disease-associated mutations on GPR56/ADGRG1,”
Basic and Clinical Pharmacology and Toxicology
, pp. 0–0, 2023, Accessed: 00, 2023. [Online]. Available: https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85153478794&origin=inward.