Affective disorders arise from abnormal responses of the brain to prolonged exposure to challenging environmental stimuli. Recent work identified the orphan receptor GPR158 as a molecular link between chronic stress and depression. Here we reveal a non-canonical mechanism by which GPR158 exerts its effects on stress-induced depression by the complex formation with Regulator of G protein Signaling 7 (RGS7). Chronic stress promotes membrane recruitment of RGS7 via GPR158 in the medial prefrontal cortex (mPFC). The resultant complex suppresses homeostatic regulation of cAMP by inhibitory GPCRs in the region. Accordingly, RGS7 loss in mice induces an antidepressant-like phenotype and resiliency to stress, whereas its restoration within the mPFC is sufficient to rescue this phenotype in a GPR158-dependent way. These findings mechanistically link the unusual orphan receptor-RGS complex to a major stress mediator, the cAMP system and suggest new avenues for pharmacological interventions in affective disorders.

中文翻译：

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由RGS7复合物调节的稳态cAMP可控制与抑郁相关的行为。

情感障碍源于大脑对长时间暴露于挑战性环境刺激的异常反应。最近的工作将孤儿受体GPR158鉴定为慢性应激和抑郁症之间的分子联系。在这里，我们揭示了一种非规范机制，GPR158通过与G蛋白信号传导7（RGS7）调节剂的复合物形成，对应激诱导的抑郁症发挥作用。慢性应激会通过前额内侧皮层（mPFC）中的GPR158促进RGS7的膜募集。所得复合物通过该区域中的抑制性GPCR抑制cAMP的稳态调节。因此，小鼠中RGS7的丢失诱导了抗抑郁样表型和对压力的适应性，而其在mPFC中的恢复足以以GPR158依赖性方式拯救该表型。