SNX14 is a bifunctional negative regulator for neuronal 5-HT6 receptor signaling.

The 5-hydroxytryptamine (5-HT, also known as serotonin) subtype 6 receptor (5-HT6R, also known as HTR6) plays roles in cognition, anxiety and learning and memory disorders, yet new details concerning its regulation remain poorly understood. In this study, we found that 5-HT6R directly interacted with SNX14 and that this interaction dramatically increased internalization and degradation of 5-HT6R. Knockdown of endogenous SNX14 had the opposite effect. SNX14 is highly expressed in the brain and contains a putative regulator of G-protein signaling (RGS) domain. Although its RGS domain was found to be non-functional as a GTPase activator for Gαs, we found that it specifically bound to and sequestered Gαs, thus inhibiting downstream cAMP production. We further found that protein kinase A (PKA)-mediated phosphorylation of SNX14 inhibited its binding to Gαs and diverted SNX14 from Gαs binding to 5-HT6R binding, thus facilitating the endocytic degradation of the receptor. Therefore, our results suggest that SNX14 is a dual endogenous negative regulator in 5-HT6R-mediated signaling pathway, modulating both signaling and trafficking of 5-HT6R.