title: SNX14 is a bifunctional negative regulator for neuronal 5-HT6 receptor signaling.
abstract: 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.
authors: Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, South Korea Biomembrane Plasticity Research Center, Seoul National University College of Medicine, Seoul 110-799, South Korea Department of Structure and Function of Neural Network, Korea Brain Research Institute, Daegu 700-100, South Korea.
authors: Chang Man
authors: CM
authors: Ha
authors: Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, South Korea Biomembrane Plasticity Research Center, Seoul National University College of Medicine, Seoul 110-799, South Korea.
authors: Daehun
authors: D
authors: Park
authors: Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, South Korea Biomembrane Plasticity Research Center, Seoul National University College of Medicine, Seoul 110-799, South Korea Neuroscience Institute, Seoul National University College of Medicine, Seoul 110-799, South Korea.
authors: Yoonju
authors: Y
authors: Kim
authors: Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, South Korea Biomembrane Plasticity Research Center, Seoul National University College of Medicine, Seoul 110-799, South Korea.
authors: Myeongsu
authors: M
authors: Na
authors: Departments of Physiology & Biophysics and Psychiatry, University of Illinois at Chicago, Jesse Brown VA Medical Center, Chicago, IL 60680, USA.
authors: Surabhi
authors: S
authors: Panda
authors: Department of Life Science, Gwangju Institute of Science and Technology, Gwangju 500-712, South Korea.
authors: Sehoon
authors: S
authors: Won
authors: Department of Anatomy, Korea University College of Medicine, Seoul 136-705, South Korea.
authors: Hyun
authors: H
authors: Kim
authors: Biomembrane Plasticity Research Center, Seoul National University College of Medicine, Seoul 110-799, South Korea.
authors: Hoon
authors: H
authors: Ryu
authors: Department of Life Science, Gwangju Institute of Science and Technology, Gwangju 500-712, South Korea.
authors: Zee Yong
authors: ZY
authors: Park
authors: Departments of Physiology & Biophysics and Psychiatry, University of Illinois at Chicago, Jesse Brown VA Medical Center, Chicago, IL 60680, USA.
authors: Mark M
authors: MM
authors: Rasenick
authors: Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, South Korea Biomembrane Plasticity Research Center, Seoul National University College of Medicine, Seoul 110-799, South Korea Neuroscience Institute, Seoul National University College of Medicine, Seoul 110-799, South Korea sunghoe@snu.ac.kr.
authors: Sunghoe
authors: S
authors: Chang
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004705:Endocytosis; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000378:metabolism; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D051381:Rats; D011985:Receptors, Serotonin / Q000378:metabolism*; D015398:Signal Transduction; D058305:Sorting Nexins / Q000378:metabolism*
chemical_list: D011985:Receptors, Serotonin; C437950:Snx14 protein, mouse; D058305:Sorting Nexins; C097216:serotonin 6 receptor; D010768:Phosphoserine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D019205:GTP-Binding Protein alpha Subunits, Gs
keywords: 5‐HT; 5‐hydroxytryptamine type 6 receptor; G protein‐coupled receptor; Guanosine triphosphatase‐activating proteins; Regulator of G protein signaling; SNX14; Sorting nexin