Functional expression of the serotonin 5‐HT<sub>7</sub> receptor in human glioblastoma cell lines

Mahé, Cécile; Bernhard, Mario; Bobirnac, Ionel; Keser, Corinna; Loetscher, Erika; Feuerbach, Dominik; Dev, Kumlesh K.; Schoeffter, Philippe

doi:10.1038/sj.bjp.0705936

Cited by 47 publications

(55 citation statements)

References 29 publications

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“…Two protein products were observed for both 5-HT 1B and 5-HT 7 receptors, between 41 and 50 kDa, and are consistent with reports of splice variants and post-translational modifications. [26][27][28][29] This conclusion is supported by observations of similar doublets in the positive control samples (Figure 2A-B). …”

supporting

confidence: 77%

“…This may represent differential regulation of 5-HT 7 receptor splicing (3 splice variants are recognized in mice), and/or post-translational modification. 26 Furthermore, although expression of 5-HT 1B and 5-HT 2A is low or undetectable in naive T cells, respectively, we find that protein and/or mRNA for these receptors is substantially increased following T-cell activation. Unlike 5-HT 7 receptors, 5-HT 1B and 5-HT 2A receptors are coupled to Gi and Gq proteins and thus likely trigger distinct signaling events in activated T cells, which potentially contribute to sustained proliferation and/or differentiation.…”

Section: -Ht Is a Cofactor For T-cell Activation 3143mentioning

confidence: 86%

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Serotonin provides an accessory signal to enhance T-cell activation by signaling through the 5-HT7 receptor

Leon‐Ponte

Ahern

O’Connell

2006

Blood

276

266

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IntroductionThe central and peripheral nervous systems can modulate immune function by releasing soluble factors such as hormones, neuropeptides, and neurotransmitters. 1,2 Serotonin (5-HT) is a classical neurotransmitter and vasoactive amine best known for its role in the regulation of variety of physiologic states and behaviors, including pain, appetite, mood, and sleep. 3 Despite these major roles for 5-HT in the central nervous system, the vast majority of 5-HT is produced in the periphery (Ͼ 90%), primarily by enterochromaffin cells in the gut. 4 Consistent with its abundance in the periphery, 5-HT is recognized as an important inflammatory mediator with significant immune-modulatory effects. 2,5 Mast cells and platelets both express the 5-HT specific transporter (SERT) which enables them to sequester 5-HT from the microenvironment. In turn, 5-HT is released in response to injury and/or inflammatory signals such as platelet activating factor, complement components (C3a and C5a), and IgE complexes. 5,6 Released 5-HT has been shown to regulate platelet aggregation 7 and to promote the accessory function of macrophages, and it is a potent eosinophil chemoattractant. 8,9 Consistent with these effects, 5-HT is implicated in the pathogenesis of inflammatory disorders, including asthma, inflammatory bowel syndrome, allergic diarrhea, and chronic eczema. 5,[10][11][12][13][14] Several studies have demonstrated that T and B lymphocytes are functionally responsive to 5-HT, implicating a role for this monoamine in the generation of adaptive immune responses. Inhibition of endogenous 5-HT synthesis can impair rodent T-cell proliferation. 2,15,16 Conversely, exogenous 5-HT is reported to suppress T-cell proliferation. 3 5-HT triggers the increased release of preformed IL-16 from CD8 ϩ T cells and can initiate delayedtype hypersensitivity reactions through the local recruitment and activation of CD4 ϩ T cells. [17][18][19] Thus, the precise role of 5-HT in modulating lymphocyte activation or function is currently ambiguous. Moreover, the identity of 5-HTRs expressed by T cells and the intracellular signaling pathways that transduce this signal remain unclear. 5-HTR signaling is complex with 7 recognized receptor subfamilies. 2 With the exception of the 5-HT 3 receptor, which is a ligand-gated ion channel, they belong to the family of 7 transmembrane G protein-coupled receptors. Both 5-HT 1 and 5-HT 2 receptor subfamilies have been implicated in signaling T cells. 3,[15][16][17]20,21 With rare exception, however, 20 most studies have only demonstrated the expression of 5-HTR gene transcripts or pharmacologic sensitivity to 5-HTR agonists or antagonists. 3 To elucidate the function of 5-HT signaling in T cells, we have made a comprehensive analysis of 5-HTR expression and signaling in primary mouse T cells. We show that naive T cells primarily express the 5-HT 7 receptor. Exogenous 5-HT leads to rapid phosphorylation of extracellular signal related kinase-1 and -2 (ERK1/2) and IB␣ in bulk naive T cells, early steps that ar...

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supporting

confidence: 77%

Section: -Ht Is a Cofactor For T-cell Activation 3143mentioning

confidence: 86%

Serotonin provides an accessory signal to enhance T-cell activation by signaling through the 5-HT7 receptor

Leon‐Ponte

Ahern

O’Connell

2006

Blood

276

266

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“…Regarding the glial origin of GBMs, these tumors exhibit receptors for a large variety of neurotransmitters [20][21][22]. Particularly, glutamate receptors, including ionic (NMDA, AMPA and Kainate) and metabotropic receptors (Gprotein-coupled-receptors) have been implicated on glioma behavior [20,21,[23][24][25][26][27][28].…”

Section: Introductionmentioning

confidence: 99%

Glutamate Promotes Cell Growth by EGFR Signaling on U-87MG Human Glioblastoma Cell Line

Schunemann

Grivicich

Regner

et al. 2009

Pathol. Oncol. Res.

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Accumulating evidences suggest that glutamate plays a key role in the proliferation and invasion of malignant glioblastoma (GBM) tumors. It has been shown that GBM cells release and exploit glutamate for proliferation and invasion through AMPA glutamate receptors. Additionally, amplification of the epidermal growth factor receptor (EGFR) gene occurs in 40-50% of GBM. Since, PI3K/Akt is considered one of the main intracellular pathways involved in EGFR activation, AKT functions could trigger EGFR signaling. Thus, we investigated whether EGFR-phospho-Akt pathway is involved on the glutamate inducing U-87MG human GBM cell line proliferation. For these purpose, we treated the U-87MG cell line with 5 to 200 mM of glutamate and assessed the number of viable cells by trypan blue dye exclusion test. An increase in cell number (50%) was found at 5 mM glutamate, while the addition of DNQX (500 microM), an antagonist of AMPA receptor, inhibited the effect of glutamate on the U87-MG cells proliferation. Also, at 5 mM glutamate we observed an increase on the EGFR and phospho-Akt contents evaluated by immunohistochemistry. Moreover, U-87MG cells treated with glutamate exhibited an increase about 2 times in the EGFR mRNA expression. While, in the presence of the anti-EGFR gefitinib (50 muM) or the PI3K inhibitor wortmannin (5 muM), the U-87MG proliferation was restored to control levels. Together, our data suggest that glutamate signaling mediated by AMPA receptor induces U-87MG human GBM cell line proliferation via EGFR-phospho-Akt pathway.

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“…Both Phases of the TEER Response to 5-HT Are Mediated through G s /cAMP-There are three splice variants of the 5-HT7 receptor (5-HT7a, -b, and -d) in humans (25,26), and previously we have reported the presence of all three splice variants in mammary epithelial cells (21). Although most accounts of 5-HT7 signaling link it to G s , there are studies showing its association with G12 (27), whose downstream effectors are Rho family GTPases and/or PKC.…”

Section: The Transient Response To 5-ht Is Mediated Through Pka-mentioning

confidence: 99%

Biphasic Regulation of Mammary Epithelial Resistance by Serotonin through Activation of Multiple Pathways

Pai

Horseman

2008

Journal of Biological Chemistry

100

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Mammary gland homeostasis and the lactation-to-involution switch are regulated by serotonin (5-hydroxytryptamine (5-HT)). Mammary epithelial tight junctions are physiological targets of 5-HT, and their disruption marks an early stage of mammary gland involution. In these studies, we have identified signal transduction mechanism employed by 5-HT during regulation of mammary gland transepithelial resistance. Transepithelial electrical resistance and tight junction protein architecture were studied in cultures of MCF10A human mammary epithelial cells. Serotonin had biphasic effects on mammary epithelial resistance. At lower concentrations and earlier time points, 5-HT potentiated epithelial transmembrane resistance, whereas at higher concentrations and later time points, 5-HT decreased transepithelial electrical resistance and disrupted tight junctions. Both the early and delayed actions of 5-HT were mediated by the 5-HT7 receptor through activation of G s /cAMP. 5-HT induced the activities of both protein kinase A and p38 mitogen-activated protein kinase. Inhibition of p38 mitogen-activated protein kinase abrogated 5-HT-induced disruption of mammary epithelial tight junctions (the delayed effect). In contrast, inhibition of protein kinase A prevented the increased epithelial resistance in response to 5-HT (the transient effect). These studies imply an integrated set of mechanisms whereby transient, modest activation of 5-HT7 promotes tight junction integrity, and sustained 5-HT7 activation drives involution by disrupting tight junctions.The complex and specialized functions of mammary glands has evolved to meet the specific nutritional needs of the newborn. The rapid and extensive development of the mammary gland leading to establishment of the highly energy-consuming lactation stage is balanced by the massive tissue remodeling and disintegration of mammary epithelial tissue during the involution stage (1-3). Dysregulation of these events has severe consequences for maternal health and infant nutrition and health as well as from the practical perspective of dairy production.Under the influence of endocrine hormones like estrogen, progesterone, and prolactin, the mammary gland reaches the fully developed alveolar stage by the end of pregnancy. However, lactation (milk synthesis and secretion) is not established until parturition, characterized by a drop in systemic progesterone levels along with a surge in the levels of prolactin and glucocorticoids (4 -8). Isolation of the alveolar lumen from interstitial and vascular spaces by closure of tight junctions is a critical cellular event that regulates milk synthesis and secretion (9 -11). The importance of tight junction closure is displayed by the complex interplay between the endocrine hormones in regulating them and thus, in turn, regulating lactation (11-13).Each alveolar unit of a lactating mammary gland is independently regulated in an autocrine-paracrine manner through a feedback system of local factors (14 -16). Absence of a suckling stimulus results in accumu...

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Functional expression of the serotonin 5‐HT₇ receptor in human glioblastoma cell lines

Cited by 47 publications

References 29 publications

Serotonin provides an accessory signal to enhance T-cell activation by signaling through the 5-HT7 receptor

Serotonin provides an accessory signal to enhance T-cell activation by signaling through the 5-HT7 receptor

Glutamate Promotes Cell Growth by EGFR Signaling on U-87MG Human Glioblastoma Cell Line

Biphasic Regulation of Mammary Epithelial Resistance by Serotonin through Activation of Multiple Pathways

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Functional expression of the serotonin 5‐HT7 receptor in human glioblastoma cell lines

Cited by 47 publications

References 29 publications

Serotonin provides an accessory signal to enhance T-cell activation by signaling through the 5-HT7 receptor

Serotonin provides an accessory signal to enhance T-cell activation by signaling through the 5-HT7 receptor

Glutamate Promotes Cell Growth by EGFR Signaling on U-87MG Human Glioblastoma Cell Line

Biphasic Regulation of Mammary Epithelial Resistance by Serotonin through Activation of Multiple Pathways

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Functional expression of the serotonin 5‐HT₇ receptor in human glioblastoma cell lines