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
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.
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.
J Cell Sci. 2015 May 1;128(9):1848-61. doi: 10.1242/jcs.169581. Epub 2015 Mar 20.
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.
5-羟色胺（5-HT，也称为血清素）6型受体（5-HT6R，也称为HTR6）在认知、焦虑以及学习和记忆障碍中发挥作用，但其调控的新细节仍知之甚少。在本研究中，我们发现5-HT6R与分选衔接蛋白14（SNX14）直接相互作用，且这种相互作用显著增加了5-HT6R的内化和降解。敲低内源性SNX14则产生相反的效果。SNX14在大脑中高度表达，并含有一个假定的G蛋白信号调节（RGS）结构域。尽管发现其RGS结构域作为Gαs的GTP酶激活剂无功能，但我们发现它能特异性结合并隔离Gαs，从而抑制下游环磷酸腺苷（cAMP）的产生。我们进一步发现，蛋白激酶A（PKA）介导的SNX14磷酸化抑制了其与Gαs的结合，并使SNX14从与Gαs结合转向与5-HT6R结合，从而促进受体的内吞降解。因此，我们的结果表明，SNX14是5-HT6R介导的信号通路中的双重内源性负调节因子，可调节5-HT6R的信号传导和转运。
