2. Academic Validation
  3. Discovery of a β-arrestin-biased CCKBR agonist that blocks CCKBR-dependent long-term potentiation

Discovery of a β-arrestin-biased CCKBR agonist that blocks CCKBR-dependent long-term potentiation

  • Nat Commun. 2025 Dec 8;16(1):10938. doi: 10.1038/s41467-025-65962-y.
Heng Shi # 1 2,  Mengfan Zhang # 1 2,  Xiaofeng Hu 1 2,  Jie Zhang 2 3,  Tao Chen 1,  Pingzhou Wu 3,  Xue Wang 1,  Shu Wei 1,  George Choy 1 2,  Stephen Temitayo Bello 1 2,  Huifeng Chen 1 2,  Chunhua Liu 4,  Yiping Guo 5,  Hongyan Sun 3,  Jufang He 6 7 8
Affiliations

Affiliations

  • 1 Department of Neuroscience, City University of Hong Kong, Kowloon, Hong Kong.
  • 2 Center of Regenerative Medicine and Health, Hong Kong Institute of Science and Innovation, Chinese Academy of Sciences, Kowloon, Hong Kong.
  • 3 Department of Chemistry, City University of Hong Kong, Kowloon, Hong Kong.
  • 4 Innovation Centre for Advanced Interdisciplinary Medicine, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510799, China.
  • 5 Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong Province, China.
  • 6 Department of Neuroscience, City University of Hong Kong, Kowloon, Hong Kong. [email protected].
  • 7 Center of Regenerative Medicine and Health, Hong Kong Institute of Science and Innovation, Chinese Academy of Sciences, Kowloon, Hong Kong. [email protected].
  • 8 Department of Biomedical Science, City University of Hong Kong, Kowloon, Hong Kong. [email protected].
  • # Contributed equally.
PMID: 41360797 DOI: 10.1038/s41467-025-65962-y
Abstract

The CCKBR agonists induce neocortical long-term potentiation of excitatory synaptic transmission and enhance memory formation, while its antagonists weaken the potentiation in the amygdala and alleviate depression-like behaviors. However, the mechanism that drives CCKBR dependent long-term potentiation remains elusive. There is also no signaling pathway-biased CCKBR Agonist to modulate the potentiation. Here, we discover a β-arrestin biased CCKBR Agonist MF-8 with IC50 = 0.9 nM. The activation of CCKBR with MF-8 fails to induce the potentiation but efficiently induces CCKBR endocytosis. Multi-Electrode Array results demonstrate that the potentiation is dependent on Gαq/11-Ca2+ and Gαs-cAMP signaling pathways. The potentiation is entirely blocked by MF-8 through β-arrestin signaling. Furthermore, MF-8 effectively inhibits the formation of cue-to-cue associative fear memory. These results reveal the signal pathway preference of the CCKBR long-term potentiation and identify a blocker of the potentiation, which provides us with broader insights into developing drugs targeting CCKBR.

Figures
Products