2. Academic Validation
  3. The C-terminal region regulates the constitutive signaling activity of GPR119: G protein recruitment

The C-terminal region regulates the constitutive signaling activity of GPR119: G protein recruitment

  • Biochem Pharmacol. 2025 Jul 3:241:117095. doi: 10.1016/j.bcp.2025.117095.
Dingfan Xu 1,  Yuxia Qian 1,  Ruixue Li 2,  Sheng Ye 3,  Anna Qiao 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Synthetic Biology, Haihe Laboratory of Sustainable Chemical Transformations, Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, Faculty of Medicine, School of Life Sciences, Tianjin University, Tianjin 300072, China.
  • 2 Tianjin Medical University, 22 Meteorological Tai Road, Heping District, Tianjin 300070, China.
  • 3 State Key Laboratory of Synthetic Biology, Haihe Laboratory of Sustainable Chemical Transformations, Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, Faculty of Medicine, School of Life Sciences, Tianjin University, Tianjin 300072, China; Life Sciences Institute, Zhejiang University, Hangzhou 310058 Zhejiang, China. Electronic address: sye@tju.edu.cn.
  • 4 State Key Laboratory of Synthetic Biology, Haihe Laboratory of Sustainable Chemical Transformations, Tianjin Key Laboratory of Function and Application of Biological Macromolecular Structures, Faculty of Medicine, School of Life Sciences, Tianjin University, Tianjin 300072, China. Electronic address: anna.qiao@tju.edu.cn.
PMID: 40617490 DOI: 10.1016/j.bcp.2025.117095
Abstract

G protein-coupled receptor 119 (GPR119), a glucose-dependent insulinotropic receptor, modulates glucose homeostasis. The complexity and diversity of GPR119 signaling, closely associated with its C-terminal domain, may hinder the development of selective drugs and contribute to off-target effects. This study systematically examined the function of the C-terminal domain using amino acid deletions and site-directed mutagenesis, assessing cyclic adenosine monophosphate (cAMP) accumulation, the recruitment of Gs protein, β-arrestin 1 (βarr1), and β-arrestin 2 (βarr2). We initially conducted a broad screening through truncations of 9, 18, 27, and 36 Amino acids, followed by targeted single-amino-acid deletion analyses. These results revealed that the 15-amino-acid truncation was essential for Gs protein recruitment and cAMP accumulation. Protein Purification results revealed that truncation of the C-terminal domain did not affect GPR119-Gs-Gβγ complex formation. We further demonstrated that the C-terminal proximal phosphorylation motif was essential for the recruitment of Gs protein, βarr1, and βarr2. Notably, phosphorylation motifs in the C-terminal domains of Trace Amine-Associated Receptor 1 (TAAR1) and β-2 Adrenergic Receptor (β2AR) displayed distinct differences in the Gs protein-mediated cAMP accumulation. These findings improve our understanding of GPCR signaling's diversity and complexity, offering new insights for the development of GPR119-targeted therapeutics.

Keywords

C-terminal domain; GPR119; Phosphorylation; Signaling complexity.

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