SNX14 is a bifunctional negative regulator for neuronal 5-HT<inf>6</inf> receptor signaling

Chang Man Ha, Daehun Park, Yoonju Kim, Myeongsu Na, Surabhi Panda, Sehoon Won, Hyun Kim, Hoon Ryu, Zee Yong Park, Mark M. Rasenick, Sunghoe Chang

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

The 5-hydroxytryptamine (5-HT, also known as serotonin) subtype 6 receptor (5-HT<inf>6</inf>R, 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-HT<inf>6</inf>R directly interacted with SNX14 and that this interaction dramatically increased internalization and degradation of 5-HT<inf>6</inf>R. 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-HT<inf>6</inf>R binding, thus facilitating the endocytic degradation of the receptor. Therefore, our results suggest that SNX14 is a dual endogenous negative regulator in 5-HT<inf>6</inf>R-mediated signaling pathway, modulating both signaling and trafficking of 5-HT<inf>6</inf>R.

Original languageEnglish
Pages (from-to)1848-1861
Number of pages14
JournalJournal of Cell Science
Volume128
Issue number9
DOIs
Publication statusPublished - 2015

Fingerprint

GTP-Binding Proteins
GTP Phosphohydrolase Activators
Serotonin
Learning Disorders
Memory Disorders
Cyclic AMP-Dependent Protein Kinases
Anxiety Disorders
Cognition
Phosphorylation
Brain
serotonin 6 receptor
Protein Domains

Keywords

  • 5-HT
  • 5-hydroxytryptamine type 6 receptor
  • G protein-coupled receptor
  • Guanosine triphosphataseactivating proteins
  • Regulator of G protein signaling
  • SNX14
  • Sorting nexin

ASJC Scopus subject areas

  • Cell Biology

Cite this

Ha, C. M., Park, D., Kim, Y., Na, M., Panda, S., Won, S., ... Chang, S. (2015). SNX14 is a bifunctional negative regulator for neuronal 5-HT<inf>6</inf> receptor signaling. Journal of Cell Science, 128(9), 1848-1861. https://doi.org/10.1242/jcs.169581

SNX14 is a bifunctional negative regulator for neuronal 5-HT<inf>6</inf> 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.

In: Journal of Cell Science, Vol. 128, No. 9, 2015, p. 1848-1861.

Research output: Contribution to journalArticle

Ha, CM, Park, D, Kim, Y, Na, M, Panda, S, Won, S, Kim, H, Ryu, H, Park, ZY, Rasenick, MM & Chang, S 2015, 'SNX14 is a bifunctional negative regulator for neuronal 5-HT<inf>6</inf> receptor signaling', Journal of Cell Science, vol. 128, no. 9, pp. 1848-1861. https://doi.org/10.1242/jcs.169581
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. / SNX14 is a bifunctional negative regulator for neuronal 5-HT<inf>6</inf> receptor signaling. In: Journal of Cell Science. 2015 ; Vol. 128, No. 9. pp. 1848-1861.
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