Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Rahman MA

PROVIDER: S-EPMC5547219 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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

Rahman Md Ataur MA Kim Hanna H Lee Kang Ho KH Yun Hyung-Mun HM Hong Jung-Hwa JH Kim Youngjae Y Choo Hyunah H Park Mikyoung M Rhim Hyewhon H

Molecules and cells 20170630 7

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 incr ...[more]

PMID: 28681593

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Project description:Background5-Hydroxytryptamine (5-HT) receptors 1B, 1D and 1F have key roles in migraine pharmacotherapy. Selective agonists targeting these receptors, such as triptans and ditans, are effective in aborting acute migraine attacks and inhibit the in vivo release of calcitonin gene-related peptide (CGRP) in human and animal models. The study aimed to examine the localization, genetic expression and functional aspects of 5- HT1B/1D/1F receptors in the trigeminal system in order to further understand the molecular sites of action of triptans (5-HT1B/1D) and ditans (5-HT1F).MethodsUtilizing immunohistochemistry, the localization of 5-HT and of 5-HT1B/1D/1F receptors was examined in rat trigeminal ganglion (TG) and combined with quantitative polymerase chain reaction to quantify the level of expression for 5-HT1B/1D/1F receptors in the TG. The functional role of these receptors was examined ex vivo with a capsaicin/potassium induced 5-HT and CGRP release.Results5-HT immunoreactivity (ir) was observed in a minority of CGRP negative C-fibres, most neuron somas and faintly in A-fibres and Schwann cell neurolemma. 5-HT1B/1D receptors were expressed in the TG, while the 5-HT1F receptor displayed a weak ir. The 5-HT1D receptor co-localized with receptor activity-modifying protein 1 (RAMP1) in Aδ-fibres in the TG, while 5-HT1B-ir was weakly expressed and 5-HT1F-ir was not detected in these fibres. None of the 5-HT1 receptors co-localized with CGRP-ir in C-fibres. 5-HT1D receptor mRNA was the most prominently expressed, followed by the 5-HT1B receptor and lastly the 5-HT1F receptor. The 5-HT1B and 5-HT1D receptor antagonist, GR127935, could reverse the inhibitory effect of Lasmiditan (a selective 5-HT1F receptor agonist) on CGRP release in the soma-rich TG but not in soma-poor TG or dura mater. 5-HT release in the soma-rich TG, and 5-HT content in the baseline samples, negatively correlated with CGRP levels, showing for the first time a physiological role for 5-HT induced inhibition.ConclusionThis study reveals the presence of a subgroup of C-fibres that store 5-HT. The data shows high expression of 5-HT1B/1D receptors and suggests that the 5-HT1F receptor is a relatively unlikely target in the rat TG. Furthermore, Lasmiditan works as a partial agonist on 5-HT1B/1D receptors in clinically relevant dose regiments.

Dataset Information

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

Publications

5-Hydroxytryptamine 6 Receptor (5-HT<sub>6</sub>R)-Mediated Morphological Changes via RhoA-Dependent Pathways.

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