Peroxiredoxin 6 mediates Gαi protein-coupled receptor inactivation by cJun kinase.

This comment is coauthored by Ted Price, Head of Neuroscience, UT Dallas; Scott Dax, CSO, CerSci Therapeutics and Lucas Rodriguez, CEO, CerSci Therapeutics

The Schattauer et al. paper tackles an important question in pharmacology: How do receptors become desensitized when they interact with ligands? While the beta-arrestin pathway is very well known, it is clear that there are other mechanisms that can achieve a similar response and these pathways likely play a key role in drug tolerance and other adverse effects of GPCR ligands. In this paper the Chavkin lab identifies a new biochemical partner for several GPCRs, including the kappa and mu opioid receptors and the D2 dopamine receptor. This partner, PRDX6, links receptor conformational change to the induction of reactive oxygen species, and potentially other reactive species, like reactive nitrogen species, and biochemical alteration of Galphai proteins that are key to transducing the cellular response for these receptors. This new insight into the biochemistry of these receptors creates a unique opportunity for regulating the cellular response to ligands and suggests that tolerance, and other negative effects of drugs, may be blocked by inhibiting PRDX6 or interfering with reactive oxygen or (potentially) nitrogen species signaling. This is critical because many important analgesics target these opioid receptors and tolerance limits the clinical utility of these compounds and may be linked to opioid-induced hyperalgesia. While it is still obviously too early to determine the ultimate impact of the work, it is our opinion that this could open new avenues to enhance the efficacy of a wide range of drugs that target GPCRs that couple to Galphai.