Homeostatic cAMP regulation by the RGS7 complex controls depression-related behaviors

Neuropsychopharmacology. 2019 Feb;44(3):642-653. doi: 10.1038/s41386-018-0238-y. Epub 2018 Oct 11.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / physiology*
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Depression / etiology
  • Depression / metabolism*
  • Disease Models, Animal
  • Female
  • Homeostasis / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Prefrontal Cortex / metabolism*
  • RGS Proteins / deficiency
  • RGS Proteins / metabolism*
  • Receptors, G-Protein-Coupled / metabolism*
  • Stress, Psychological / complications
  • Stress, Psychological / metabolism*


  • GPR158 protein, mouse
  • RGS Proteins
  • Receptors, G-Protein-Coupled
  • Rgs7 protein, mouse
  • Cyclic AMP-Dependent Protein Kinases