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SNX14 is a bifunctional negative regulator for neuronal 5‐HT<sub>6</sub> receptor signaling
Ha, Chang Man,Park, Daehun,Kim, Yoonju,Na, Myeongsu,Panda, Surabhi,Won, Sehoon,Kim, Hyun,Ryu, Hoon,Park, Zee Yong,Rasenick, Mark M.,Chang, Sunghoe The Company of Biologists Limited 2015 Journal of cell science Vol.128 No.9
<P>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 Gas, we found that it specifically bound to and sequestered Gas, thus inhibiting downstream cAMP production. We further found that protein kinase A (PKA)-mediated phosphorylation of SNX14 inhibited its binding to Gas and diverted SNX14 from Gas 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.</P>