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

Journal of Cell Science
Chang Man HaSunghoe Chang

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.

References

May 28, 1993·Biochemical and Biophysical Research Communications·M RuatJ C Schwartz
Jun 3, 2000·Annual Review of Pharmacology and Toxicology·L De VriesM G Farquhar
Nov 7, 2000·The Journal of Biological Chemistry·M L CunninghamT K Harden
Aug 14, 2001·Developmental Dynamics : an Official Publication of the American Association of Anatomists·P CarrollS Alonso
Jul 18, 2002·Nature Reviews. Drug Discovery·Richard R Neubig, David P Siderovski
Dec 4, 2002·Nature Reviews. Molecular Cell Biology·Carolyn A Worby, Jack E Dixon
May 3, 2003·Life Sciences·Robert J Donati, Mark M Rasenick
Jul 12, 2005·Pharmacology & Therapeutics·Ellen S Mitchell, John F Neumaier
Nov 19, 2005·Science·Maria Domenica CastelloneJ Silvio Gutkind
Jan 13, 2006·British Journal of Pharmacology·Stephen J Hill
Jan 13, 2006·British Journal of Pharmacology·Graeme Milligan, Evi Kostenis
Dec 26, 2006·The Journal of Biological Chemistry·Hyung-Mun YunHyewhon Rhim
Dec 29, 2006·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Ellen S MitchellJohn F Neumaier
Feb 20, 2007·Annual Review of Physiology·Scott M DeWireSudha K Shenoy
Aug 12, 2008·Current Topics in Medicinal Chemistry·Werner J Geldenhuys, Cornelis J Van der Schyf
Jun 9, 2011·Current Medicinal Chemistry·D MarazzitiF Borsini
Sep 21, 2011·Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences·Hyunwoo ChoiZee-Yong Park
Oct 3, 2012·EMBO Molecular Medicine·Julie MeffrePhilippe Marin
Jun 2, 2014·Nature Chemical Biology·Fanny DuhrSéverine Chaumont-Dubel
Dec 3, 2014·American Journal of Human Genetics·Anna C ThomasPhilip Stanier

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Citations

Jun 23, 2015·Journal of Medicinal Chemistry·Delphine KarilaChristophe Rochais
Dec 8, 2016·Behavioural Pharmacology·Alfredo Meneses
Oct 25, 2017·Journal of Cell Science·Nicole Heucken, Rumen Ivanov
May 30, 2020·Translational Psychiatry·R SarviahoH Lohi
Mar 28, 2017·Reviews in the Neurosciences·Alfredo Meneses
Nov 30, 2018·Frontiers in Pharmacology·Nicolas B SeneseJohn R Traynor
Mar 17, 2019·Clinical Science·Jian YangChunyu Zeng
Feb 13, 2020·Science Signaling·Camille N PujolSéverine Chaumont-Dubel
Oct 23, 2020·Journal of Cellular Physiology·Lu YangJing Zhong
Mar 4, 2021·International Journal of Molecular Sciences·Bibhas AmatyaPedro A Jose
May 2, 2021·Molecular Neurobiology·Neide VieiraNuno Sousa

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