背景:第二代抗精神病药(SGAs)是严重精神疾病的一线治疗方法。通常,个别患者仅受益于一些SGA,而不是其他。这种治疗效果不可预测性的潜在机制仍不清楚。所有SGA结合D3多巴胺受体(D3R)并且传统上被认为是多巴胺受体信号传导的拮抗剂。
方法:这里,我们使用双光子钙成像的组合,体外信号测定,和小鼠行为来评估SGA在D3R处的信号传导。
结果:我们报告了一些临床上重要的SGAs在D3R时作为抑制素-3-激动剂起作用,导致位于前额叶皮质锥体细胞动作电位起始位点的钙通道的调节。我们进一步表明,用抑制蛋白-3-激动剂-SGA进行慢性治疗,但不是拮抗剂SGA,通过G蛋白偶联受体相关分选蛋白1(GASP1)的内吞受体降解来消除D3R功能。
结论:这些结果表明D3R-抑制蛋白-3信号传导是SGA变异性的来源,强调在药物作用表征中包括arrestin-3信号传导的重要性。此外,他们提示,在慢性SGA治疗期间发生的内吞后受体转运可能有助于治疗疗效.
Second-generation antipsychotics (SGAs) are frontline treatments for serious mental illness. Often, individual patients benefit only from some SGAs and not others. The mechanisms underlying this unpredictability in treatment efficacy remain unclear. All SGAs bind the dopamine D3 receptor (D3R) and are traditionally considered antagonists for dopamine receptor signaling.
Here, we used a combination of two-photon calcium imaging, in vitro signaling assays, and mouse behavior to assess signaling by SGAs at D3R.
We report that some clinically important SGAs function as arrestin-3 agonists at D3R, resulting in modulation of calcium channels localized to the site of action potential initiation in prefrontal cortex pyramidal neurons. We further show that chronic treatment with an arrestin-3 agonist SGA, but not an antagonist SGA, abolishes D3R function through postendocytic receptor degradation by GASP1 (G protein-coupled receptor-associated sorting protein-1).
These results implicate D3R-arrestin-3 signaling as a source of SGA variability, highlighting the importance of including arrestin-3 signaling in characterizations of drug action. Furthermore, they suggest that postendocytic receptor trafficking that occurs during chronic SGA treatment may contribute to treatment efficacy.