Distinctive biochemical properties of the μ-opioid receptor-corticotropin- releasing factor CRF1 receptor heterotetramer

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Heteromerization of Gs with Gi protein-coupled receptors has been suggested to be necessary to sustain the canonical Gi-Gs antagonistic interaction at adenylyl cyclase (AC). These heteromers have a tetrameric quaternary structure, composed by two homodimers each one coupled to its corresponding G protein. We describe the heterotetramer formed by the Gi-coupled μ-opioid receptor (MOR) and the Gs-coupled corticotropin releasing factor CRF 1 receptor (CRF 1 R), which also sustains a canonical interaction at AC and reciprocal allosteric interactions between MOR and CRF 1 R ligands. In addition, we found that CRF 1 R can also couple to Gq proteins in the MOR-CRF 1 R heteromer, providing the frame for also canonical Gi-Gq antagonistic interactions that include other effectors, such as phospholipase C and its Ca 2 + -dependent signaling, and which control glutamate release in the central amygdala (CeA). The specific pharmacodynamic properties of the MOR-CRF 1 R heteromer, including its sensitivity to S-methadone, as well as its localization in the CeA suggest it might represent a significant pharmacological target for the analgesic, antistressor and antidepressant effects of opioids and the hyperalgesia of opioid withdrawal. • μ-opioid receptor (MOR) and CRF 1 receptor (CRF 1 R) form heterotetramers. • In the MOR-CRF 1 R heterotetramer, MOR couples to Gi and CRF 1 R couples to Gs or Gq. • Gi-Gq-MOR-CRF 1 R heterotetramers control glutamate release in the central amygdala. • S-methadone does not lose its efficacy in the MOR-CRF 1 R heterotetramer. • MOR-CRF 1 R can be target for the antistressor and antidepressant effects of opioids.

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