4.5 Article

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

Journal

JOURNAL OF CELL SCIENCE
Volume 128, Issue 9, Pages 1848-1861

Publisher

COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/jcs.169581

Keywords

SNX14; G protein-coupled receptor; Regulator of G protein signaling; Sorting nexin; Guanosine triphosphatase-activating proteins; 5-hydroxytryptamine type 6 receptor; 5-HT

Categories

Funding

  1. National Research Foundation (NRF) of Korea [SRC 20100029395, 20100029395]
  2. Education and Research Encouragement Fund of Seoul National University Hospital
  3. Basic Science Research Program [20100022375]
  4. KBRI research program [20140006, 20150002]
  5. US Public Health Service [MH07800]
  6. US Veteran's Administration [BX001149]

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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.

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