@inbook{c9e1df095bf94a7a9993e8a99273fb50,
title = "Spatial regulation of GPR64/ADGRG2 signaling by β-arrestins and GPCR kinases",
abstract = "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.",
keywords = "Adhesion GPCR, Endocytosis, G protein, GPCR kinase",
author = "Pedram Azimzadeh and Talamantez-Lyburn, {Sarah C.} and Chang, {Katarina T.} and Asuka Inoue and Nariman Balenga",
note = "Funding Information: We acknowledge the assistance from the staff of the Confocal Microscopy Core at the University of Maryland School of Medicine, Center for Innovative Biomedical Resources, Baltimore, Maryland. We are grateful to Dr. John Olson for the infrastructure support. This work was supported by the American Cancer Society Institutional Research Grant and Research Starter Grant in Translational Medicine and Therapeutics from the PhRMA Foundation to N.B. A.I. was supported by the PRIME JP18gm5910013h and the LEAP JP18gm0010004h from the Japan Agency for Medical Research and Development (AMED). S.C.T.-L was supported by the Meyerhoff Fellows Program. Publisher Copyright: {\textcopyright} 2019 New York Academy of Sciences.",
year = "2019",
doi = "10.1111/nyas.14227",
language = "English",
series = "Annals of the New York Academy of Sciences",
publisher = "Blackwell Publishing Inc.",
number = "1",
pages = "26--43",
booktitle = "Annals of the New York Academy of Sciences",
edition = "1",
}