Spatial regulation of GPR64/ADGRG2 signaling by β-arrestins and GPCR kinases

Pedram Azimzadeh, Sarah C. Talamantez-Lyburn, Katarina T. Chang, Asuka Inoue, Nariman Balenga

Research output: Chapter in Book/Report/Conference proceedingChapter

12 Citations (Scopus)


Mechanisms of activation, signaling, and trafficking of adhesion G protein–coupled receptors (aGPCRs) have remained largely unknown. Several aGPCRs, including GPR56/ADGRG1 and GPR64/ADGRG2, show increased activity in the absence of their N-terminal fragment (NTF). This constitutive signaling is plausibly caused by the binding of extracellular N-terminal 15–25 amino acid–long tethered agonist to extracellular domains of the cognate aGPCRs. To test the role of NTF and tethered agonist in GPR64 signaling and endocytosis, we generated mutants that lack either NTF alone (∆NTF) or NTF and tethered agonist (P622). We discover that unlike full-length GPR64, ∆NTF and P622 mutants interact with β-arrestin1 and β-arrestins2 and are constitutively internalized in steady states. However, only ∆NTF shows exaggerated basal activation of the Gαs–cAMP–CRE signaling cascade. Neither ∆NTF nor P622 shows constitutive activation of the Gα13–SRE pathway, but both mutants respond to exogenously added agonistic peptide via CRE and SRE. GPCR kinases and dynamin mediate the constitutive internalization of ∆NTF and P622 to early endosomes, where ∆NTF constantly induces CRE. These data suggest that NTF not only shields the tethered agonist to prevent G protein signaling but also confers a conformation that inhibits the interaction with β-arrestins and the consequent endocytosis and sustained signaling from endosomes.

Original languageEnglish
Title of host publicationAnnals of the New York Academy of Sciences
PublisherBlackwell Publishing Inc.
Number of pages18
Publication statusPublished - 2019

Publication series

NameAnnals of the New York Academy of Sciences
ISSN (Print)0077-8923
ISSN (Electronic)1749-6632


  • Adhesion GPCR
  • Endocytosis
  • G protein
  • GPCR kinase

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • History and Philosophy of Science


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