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
  • 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.

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