The serotonin receptor 5-HT₆R is an important G-protein-coupled receptor (GPCR) that involved in essential functions within the central and peripheral nervous systems and is linked to various psychiatric disorders. Selective activation of 5-HT₆R promotes neural stem cell regeneration activity. As a 5-HT₆R selective agonist, 2-(5 chloro-2-methyl-1H-indol-3-yl)-N, N-dimethylethanolamine (ST1936) has been widely used to investigate the functions of the 5-HT₆R. The molecular mechanism of how ST1936 is recognized by 5-HT₆R and how it effectively couples with Gs remain unclear. Here, we reconstituted the ST1936-5-HT₆R-Gs complex in vitro and solved its cryo-electron microscopy structure at 3.1 Å resolution. Further structural analysis and mutational studies facilitated us to identify the residues of the Y310^7.43 and "toggle switch" W281^6.48 of the 5-HT₆R contributed to the higher efficacy of ST1936 compared with 5-HT. By uncovering the structural foundation of how 5-HT₆R specifically recognizes agonists and elucidating the molecular process of G protein activation, our discoveries offer valuable insights and pave the way for the development of promising 5-HT₆R agonists.

01 Jul 2017·Molecules and CellsQ3 · BIOLOGY

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

Q3 · BIOLOGY

Article

Author: Hong, Jung-Hwa ; Rahman, Md Ataur ; Park, Mikyoung ; Rhim, Hyewhon ; Kim, Hanna ; Lee, Kang Ho ; Yun, Hyung-Mun ; Choo, Hyunah ; Kim, Youngjae

The 5-HT₆R 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-HT₆Rs and brain functions remains poorly understood. Here, we examined the effects of 5-HT₆R-mediated cell morphological changes using immunocytochemistry, Western blot, and live-cell imaging assays. Our results showed that the activation of 5-HT₆Rs caused morphological changes and increased cell surface area in HEK293 cells expressing 5-HT₆Rs. 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-HT₆Rs 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-HT₆R antagonist, SB258585. Taken together, our results show that 5-HT₆R plays an important role in the regulation of cell morphology via a RhoA-dependent pathway in mammalian cell lines and primary neurons.

01 Jul 2015·Journal of PsychopharmacologyQ3 · MEDICINE

Effects of ST1936, a selective serotonin-6 agonist, on electrical activity of putative mesencephalic dopaminergic neurons in the rat brain

Q3 · MEDICINE

Article

Author: Di Matteo, Vincenzo ; Poggi, Andreina ; Borsini, Franco ; Bordi, Fabio

The serotonin-6 (5-HT6) receptor is the most recently discovered serotonin receptor, and it represents an increasingly promising target for improving cognition in both normal and disease states. Recently, a new selective 5-HT6 receptor agonist, 2-(5 chloro-2-methyl-1H-indol-3-yl)-N,N-dimethylethanamine (ST1936), with nanomolar affinity for 5-HT6 receptors was described. We performed in-vivo electrophysiological studies to investigate the physiological role of 5-HT6 receptors in the control of the function of the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA). Extracellular single-unit recordings were performed from putative dopamine-containing neurons in the SNc and VTA of anesthetised rats. In the SNc, acute systemic administration of ST1936 had no effects on basal firing activity of these dopamine neurons; however, in the VTA, ST1936 induced either dose-related increases (45% of cells) or decreases in basal activity of these dopaminergic neurons. Local application of ST1936 into the VTA caused excitation in all of the dopamine neurons, but had no effects on non-dopamine VTA neurons. Both effects of systemic and microiontophoretic ST1936 were completely reversed by the potent and selective 5-HT6 receptor antagonist 5-chloro-N-(4-methoxy-3-piperazin-1-ylphenyl)-3-methyl-2- benzothiophene-sulfonamide (SB271046). Systemic application of another 5-HT6 agonist, 2-(1-{6-chloroimidazo[2,1-b] [1,3]thiazole-5-sulfonyl}-1H-indol-3-yl)ethan-1-amine (WAY-181187), induced dose-dependent inhibition of these VTA dopaminergic neurons. ST1936 and WAY-181187 appear to have different effects on these VTA dopaminergic neurons, potentially due to different mechanisms of action or to the complexity of 5-HT6 receptor functions. Our data demonstrate the need for further investigations into the use of 5-HT6 receptor agonists to control cognitive disfunction, such as in schizophrenia and depression.

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Indication	Highest Phase	Country/Location	Organization	Date
Depressive Disorder	Discovery	IT	Sigma-Tau Industrie Farmaceutiche Riunite SpA	-

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