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http://dx.doi.org/10.14348/molcells.2017.0080

5-Hydroxytryptamine 6 Receptor (5-HT6R)-Mediated Morphological Changes via RhoA-Dependent Pathways  

Rahman, Md. Ataur (Center for Neuroscience, Korea Institute of Science and Technology)
Kim, Hanna (Center for Functional Connectomics, Korea Institute of Science and Technology)
Lee, Kang Ho (Center for Neuroscience, Korea Institute of Science and Technology)
Yun, Hyung-Mun (Center for Neuroscience, Korea Institute of Science and Technology)
Hong, Jung-Hwa (Center for Functional Connectomics, Korea Institute of Science and Technology)
Kim, Youngjae (Center for Neuro-Medicine, Korea Institute of Science and Technology)
Choo, Hyunah (Center for Neuro-Medicine, Korea Institute of Science and Technology)
Park, Mikyoung (Center for Functional Connectomics, Korea Institute of Science and Technology)
Rhim, Hyewhon (Center for Neuroscience, Korea Institute of Science and Technology)
Publication Information
Molecules and Cells / v.40, no.7, 2017 , pp. 495-502 More about this Journal
Abstract
The $5-HT_6R$ has been considered as an attractive therapeutic target in the brain due to its exclusive expression in the brain. However, the mechanistic linkage between $5-HT_6Rs$ and brain functions remains poorly understood. Here, we examined the effects of $5-HT_6R$-mediated cell morphological changes using immunocytochemistry, Western blot, and live-cell imaging assays. Our results showed that the activation of $5-HT_6Rs$ caused morphological changes and increased cell surface area in HEK293 cells expressing $5-HT_6Rs$. Treatment with 5-HT specifically increased RhoA-GTP activity without affecting other Rho family proteins, such as Rac1 and Cdc42. Furthermore, live-cell imaging in hippocampal neurons revealed that activation of $5-HT_6Rs$ using a selective agonist, ST1936, increased the density and size of dendritic protrusions along with the activation of RhoA-GTP activity and that both effects were blocked by pretreatment with a selective $5-HT_6R$ antagonist, SB258585. Taken together, our results show that $5-HT_6R$ plays an important role in the regulation of cell morphology via a RhoA-dependent pathway in mammalian cell lines and primary neurons.
Keywords
$5-HT_6R$; dendritic protrusions; live-cell imaging; morphology; serotonin; RhoA-GTP;
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1 Cho, E., Kim, D.H., Hur, Y.N., Whitcomb, D. J., Regan, P., Hong, J.H., and Park, M. (2015). Cyclin Y inhibits plasticity-induced AMPA receptor exocytosis and LTP. Sci. Rep. 5, 12624.   DOI
2 Deraredj Nadim, W., Chaumont-Dubel, S., Madouri, F., Cobret, L., De Tauzia, M.L., Zajdel, P., and Morisset-Lopez, S. (2016). Physical interaction between neurofibromin and serotonin 5-HT6 receptor promotes receptor constitutive activity. Proc. Natl. Acad. Sci. USA 113, 12310-12315.   DOI
3 Duhr, F., Deleris, P., Raynaud, F., Seveno, M., Morisset-Lopez, S., Mannoury la Cour, C., and Chaumont-Dubel, S. (2014). Cdk5 induces constitutive activation of 5-HT6 receptors to promote neurite growth. Nat. Chem. Biol. 10, 590-597.   DOI
4 Filip, M., and Bader, M. (2009). Overview on 5-HT receptors and their role in physiology and pathology of the central nervous system. Pharmacol. Rep. 61, 761-777.   DOI
5 Fone, K.C.F. (2008). An update on the role of the 5-hydroxytryptamine6 receptor in cognitive function. Neuropharmacology 55, 1015-1022.   DOI
6 Jacobshagen, M., Niquille, M., Chaumont-Dubel, S., Marin, P., and Dayer, A. (2014). The serotonin 6 receptor controls neuronal migration during corticogenesis via a ligand-independent Cdk5-dependent mechanism. Development 141, 3370-3377.   DOI
7 Jatho, A., Hartmann, S., Kittana, N., Mugge, F., Wuertz, C.M., Tiburcy, M., and Lutz, S. (2015). RhoA ambivalently controls prominent myofibroblast characteritics by involving distinct signaling routes. PloS One 10, e0137519.   DOI
8 Kim, S., Yun, H.M., Baik, J.H., Chung, K.C., Nah, S.Y., and Rhim, H. (2007). Functional interaction of neuronal Cav1.3 L-type calcium channel with ryanodine receptor type 2 in the rat hippocampus. J. Biol. Chem. 282, 32877-32889.   DOI
9 Kvachnina, E., Liu, G., Dityatev, A., Renner, U., Dumuis, A., Richter, D.W., and Ponimaskin, E.G. (2005). 5-HT7 receptor is coupled to G alpha subunits of heterotrimeric G12-protein to regulate gene transcription and neuronal morphology. J. Neurosci. 25, 7821-7830.   DOI
10 Kim, S.H., Kim, D.H., Lee, K. H., Im, S.K., Hur, E.M., Chung, K.C., and Rhim, H. (2014). Direct interaction and functional coupling between human 5-HT6 receptor and the light chain 1 subunit of the microtubule-associated protein 1B (MAP1B-LC1). PloS One 9, e91402.   DOI
11 Lin, T., Zeng, L., Liu, Y., DeFea, K., Schwartz, M.A., Chien, S., and Shyy, J.Y.J. (2003). Rho-ROCK-LIMK-cofilin pathway regulates shear stress activation of sterol regulatory element binding proteins. Circ. Res. 92, 1296-1304.   DOI
12 Lorke, D.E., Lu, G., Cho, E., and Yew, D.T. (2006). Serotonin 5-HT2A and 5-HT6 receptors in the prefrontal cortex of Alzheimer and normal aging patients. BMC Neurosci. 7, 36.   DOI
13 Mouawad, F., Tsui, H., and Takano, T. (2013). Role of Rho-GTPases and their regulatory proteins in glomerular podocyte function. Can. J. Physiol. Pharmacol. 91, 773-782.   DOI
14 Murakoshi, H., Wang, H., and Yasuda, R. (2011). Local, persistent activation of Rho GTPases during plasticity of single dendritic spines. Nature. 472, 100-104.   DOI
15 Nakayama, A.Y., Harms, M.B., and Luo, L. (2000). Small GTPases Rac and Rho in the maintenance of dendritic spines and branches in hippocampal pyramidal neurons. J. Neurosci. 20, 5329-5338.   DOI
16 Woolley, M.L., Marsden, C.A., and Fone, K.C.F. (2004). 5-ht6 receptors. Curr. Drug. Targets. CNS. Neurol. Disord. 3, 59-79.   DOI
17 Ponimaskin, E., Voyno-Yasenetskaya, T., Richter, D. W., Schachner, M., and Dityatev, A. (2007). Morphogenic signaling in neurons via neurotransmitter receptors and small GTPases. Mol. Neurobiol. 35, 278-287.   DOI
18 Quilliam, L.A., Khosravi-Far, R., Huff, S.Y., and Der, C.J. (1995). Guanine nucleotide exchange factors: activators of the Ras superfamily of proteins. Bioessays. 17, 395-404.   DOI
19 Speranza, L., Giuliano, T., Volpicelli, F., De Stefano, M.E., Lombardi, L., Chambery, A., and Perrone-Capano, C. (2015). Activation of 5-HT7 receptor stimulates neurite elongation through mTOR, Cdc42 and actin filaments dynamics. Front. Behav. Neurosci. 9, 62.
20 Yun, H.M., and Rhim, H. (2011). The serotonin-6 receptor as a novel therapeutic target. Exp. Neurol. 20, 159-168.
21 Yun, H.M., Kim, S., Kim, H.-J., Kostenis, E., Kim, J.I, Seong, J.Y., and Rhim, H. (2007). The novel cellular mechanism of human 5-HT6 receptor through an interaction with Fyn. J. Biol. Chem. 282, 5496-5505.   DOI
22 Yun, H.M., Baik, J.-H., Kang, I., Jin, C., and Rhim, H. (2010). Physical interaction of Jab1 with human serotonin 6 G-protein-coupled receptor and their possible roles in cell survival. J. Biol. Chem. 285, 10016-10029.   DOI