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<p>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 IC<sub>50</sub> = 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 Gα<sub>q/11</sub>-Ca<sup>2+</sup> and Gα<sub>s</sub>-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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月8日

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  • Heng Shi,
  • Mengfan Zhang,
  • Xiaofeng Hu,
  • Jie Zhang,
  • Tao Chen,
  • Pingzhou Wu,
  • Xue Wang,
  • Shu Wei,
  • George Choy,
  • Stephen Temitayo Bello,
  • Huifeng Chen,
  • Chunhua Liu,
  • Yiping Guo,
  • Hongyan Sun,
  • Jufang He

摘要

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.