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

研究成果: Chapter

9 被引用数 (Scopus)

抄録

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.

本文言語English
ホスト出版物のタイトルAnnals of the New York Academy of Sciences
出版社Blackwell Publishing Inc.
ページ26-43
ページ数18
1
DOI
出版ステータスPublished - 2019

出版物シリーズ

名前Annals of the New York Academy of Sciences
番号1
1456
ISSN(印刷版)0077-8923
ISSN(電子版)1749-6632

ASJC Scopus subject areas

  • 神経科学(全般)
  • 生化学、遺伝学、分子生物学(全般)
  • 科学史および科学哲学

フィンガープリント

「Spatial regulation of GPR64/ADGRG2 signaling by β-arrestins and GPCR kinases」の研究トピックを掘り下げます。これらがまとまってユニークなフィンガープリントを構成します。

引用スタイル