The orphan Gαs-coupled receptor GPR52 is expressed exclusively in the brain, predominantly in circuitry relating to symptoms of neuropsychiatric and cognitive disorders such as schizophrenia. While GPR52 agonists have displayed antipsychotic and procognitive efficacy in murine models, there remains limited evidence delineating the molecular mechanisms of these effects. Indeed, previous studies have solely reported canonical cAMP signaling and CREB phosphorylation downstream of GPR52 activation. In the present study, we demonstrated that the synthetic GPR52 agonist, 3-BTBZ, equipotently induces cAMP accumulation, ERK1/2 phosphorylation, and β-arrestin-1 and -2 recruitment in transfected HEK293T cells. In cultured frontal cortical neurons, however, 3-BTBZ-induced ERK1/2 phosphorylation was significantly more potent than cAMP signaling, with a more prolonged signaling profile than that in HEK293T cells. Furthermore, knock down of β-arrestin-2 in frontal cortical neurons abolished 3-BTBZ-induced ERK1/2 phosphorylation, but not cAMP accumulation. These results suggest a β-arrestin-2-dependent mechanism for GPR52-mediated ERK1/2 signaling, which may link to cognitive function in vivo. Finally, these findings highlight the context-dependence of GPCR signaling in recombinant cells and neurons, offering new insights into translationally relevant GPR52 signaling mechanisms.

中文翻译：

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额叶皮层神经元中 GPR52 信号传导的 β-Arrestin-2 依赖性机制。

孤儿 Gαs 偶联受体 GPR52 仅在大脑中表达，主要在与精神分裂症等神经精神和认知障碍症状相关的电路中表达。虽然 GPR52 激动剂在小鼠模型中显示出抗精神病和促认知功效，但描述这些作用的分子机制的证据仍然有限。事实上，以前的研究仅报道了 GPR52 激活下游的典型 cAMP 信号传导和 CREB ​​磷酸化。在本研究中，我们证明合成的 GPR52 激动剂 3-BTBZ 在转染的 HEK293T 细胞中等效诱导 cAMP 积累、ERK1/2 磷酸化和 β-arrestin-1 和 -2 募集。然而，在培养的额叶皮层神经元中，3-BTBZ 诱导的 ERK1/2 磷酸化明显比 cAMP 信号传导更有效，具有比 HEK293T 细胞更长时间的信号传导谱。此外，敲除额叶皮层神经元中的 β-arrestin-2 会消除 3-BTBZ 诱导的 ERK1/2 磷酸化，但不会消除 cAMP 积累。这些结果表明 GPR52 介导的 ERK1/2 信号传导存在 β-arrestin-2 依赖性机制，这可能与认知功能有关在体内。最后，这些发现强调了 GPCR 信号在重组细胞和神经元中的上下文依赖性，为翻译相关的 GPR52 信号机制提供了新的见解。