TY - JOUR
T1 - SNX14 is a bifunctional negative regulator for neuronal 5-HT6 receptor signaling
AU - Ha, Chang Man
AU - Park, Daehun
AU - Kim, Yoonju
AU - Na, Myeongsu
AU - Panda, Surabhi
AU - Won, Sehoon
AU - Kim, Hyun
AU - Ryu, Hoon
AU - Park, Zee Yong
AU - Rasenick, Mark M.
AU - Chang, Sunghoe
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
KW - 5-HT
KW - 5-hydroxytryptamine type 6 receptor
KW - G protein-coupled receptor
KW - Guanosine triphosphataseactivating proteins
KW - Regulator of G protein signaling
KW - SNX14
KW - Sorting nexin
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UR - http://www.scopus.com/inward/citedby.url?scp=84929494363&partnerID=8YFLogxK
U2 - 10.1242/jcs.169581
DO - 10.1242/jcs.169581
M3 - Article
C2 - 25795301
AN - SCOPUS:84929494363
VL - 128
SP - 1848
EP - 1861
JO - Journal of Cell Science
JF - Journal of Cell Science
SN - 0021-9533
IS - 9
ER -