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GB83, an Agonist of PAR2 with a Unique Mechanism of Action Distinct from Trypsin and PAR2-AP.
Heo, Yunkyung; Yang, Eunhee; Lee, Yechan; Seo, Yohan; Ryu, Kunhi; Jeon, Hyejin; Namkung, Wan.
  • Heo Y; College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon 21983, Korea.
  • Yang E; College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon 21983, Korea.
  • Lee Y; College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon 21983, Korea.
  • Seo Y; College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon 21983, Korea.
  • Ryu K; New Drug Development Center, Daegu Gyeongbuk Medical Innovation Foundation, Daegu 41061, Korea.
  • Jeon H; College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon 21983, Korea.
  • Namkung W; College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon 21983, Korea.
Int J Mol Sci ; 23(18)2022 Sep 13.
Article in English | MEDLINE | ID: covidwho-2039869
ABSTRACT
Protease-activated receptor 2 (PAR2) is a G-protein-coupled receptor (GPCR) activated by proteolytic cleavage of its N-terminal domain. Once activated, PAR2 is rapidly desensitized and internalized by phosphorylation and ß-arrestin recruitment. Due to its irreversible activation mechanism, some agonists that rapidly desensitized PAR2 have been misconceived as antagonists, and this has impeded a better understanding of the pathophysiological role of PAR2. In the present study, we found that GB83, initially identified as a PAR2 antagonist, is a bona fide agonist of PAR2 that induces unique cellular signaling, distinct from trypsin and PAR2-activating peptide (AP). Activation of PAR2 by GB83 markedly elicited an increase in intracellular calcium levels and phosphorylation of MAPKs, but in a delayed and sustained manner compared to the rapid and transient signals induced by trypsin and PAR2-AP. Interestingly, unlike PAR2-AP, GB83 and trypsin induced sustained receptor endocytosis and PAR2 colocalization with ß-arrestin. Moreover, the recovery of the localization and function of PAR2 was significantly delayed after stimulation by GB83, which may be the reason why GB83 is recognized as an antagonist of PAR2. Our results revealed that GB83 is a bona fide agonist of PAR2 that uniquely modulates PAR2-mediated cellular signaling and is a useful pharmacological tool for studying the pathophysiological role of PAR2.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Calcium / Receptor, PAR-2 Language: English Year: 2022 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Calcium / Receptor, PAR-2 Language: English Year: 2022 Document Type: Article