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

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 Gα_q/11-Ca²⁺ and Gα_s-cAMP signaling pathways. The potentiation is entirely blocked

SUBMITTER: Shi H 

PROVIDER: S-EPMC12686490 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature