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E Pradines,
J Hernandez-Rapp,
A Villa-Diaz,
C Dakowski,
H Ardila-Osorio,
S Haik,
B Schneider, J-M Launay,
O Kellermann,
J-M Torres,
S Mouillet-Richard
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ABSTRACT: The subversion of the normal function exerted by the cellular prion protein (PrP(C)) in neurons by pathogenic prions is assumed to have a central role in the pathogenesis of transmissible spongiform encephalopathies. Using two murine models of prion infection, the 1C11 neuronal cell line and neurospheres, we document that prion infection is associated with the constitutive activation of signaling targets normally coupled with PrP(C), including the Fyn kinase, the mitogen-associated protein kinases ERK1/2 and the CREB transcription factor. PrP(C)-dependent signaling overactivation in infected cells is associated with the recruitment of p38 and JNK stress-associated kinases. Downstream from CREB, prion-infected cells exhibit reduced activity of the matrix metalloprotease (MMP)-9. As MMP-9 catalyzes the degradation of the amyloid A-beta peptide, the decrease in MMP-9 activity in prion-infected cells causes a significant impairment of the clearance of A-beta, leading to its accumulation. By exploiting two 1C11-infected clones accumulating high or moderate levels of prions, we show that the prion-induced changes are correlated with the level of infectivity. Of note, a dose-dependent increase in A-beta levels was also found in the cerebrospinal fluid of mice inoculated with these infected clones. By demonstrating that pathogenic prions trigger increases in A-beta levels through the deviation of PrP(C) signaling, our data argue that A-beta may exacerbate prion-induced toxicity.
Cell Death & Disease 01/2013; 4:e456. · 5.33 Impact Factor
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ABSTRACT: Serotonin reuptake inhibitor (SRI) antidepressants such as fluoxetine (Prozac), promote hippocampal neurogenesis. They also increase the levels of the bcl-2 protein, whose overexpression in transgenic mice enhances adult hippocampal neurogenesis. However, the mechanisms underlying SRI-mediated neurogenesis are unclear. Recently, we identified the microRNA miR-16 as an important effector of SRI antidepressant action in serotonergic raphe and noradrenergic locus coeruleus (LC). We show here that miR-16 mediates adult neurogenesis in the mouse hippocampus. Fluoxetine, acting on serotonergic raphe neurons, decreases the amount of miR-16 in the hippocampus, which in turn increases the levels of the serotonin transporter (SERT), the target of SRI, and that of bcl-2 and the number of cells positive for Doublecortin, a marker of neuronal maturation. Neutralization of miR-16 in the hippocampus further exerts an antidepressant-like effect in behavioral tests. The fluoxetine-induced hippocampal response is relayed, in part, by the neurotrophic factor S100β, secreted by raphe and acting via the LC. Fluoxetine-exposed serotonergic neurons also secrete brain-derived neurotrophic factor, Wnt2 and 15-Deoxy-delta12,14-prostaglandin J2. These molecules are unable to mimic on their own the action of fluoxetine and we show that they act synergistically to regulate miR-16 at the hippocampus. Of note, these signaling molecules are increased in the cerebrospinal fluid of depressed patients upon fluoxetine treatment. Thus, our results demonstrate that miR-16 mediates the action of fluoxetine by acting as a micromanager of hippocampal neurogenesis. They further clarify the signals and the pathways involved in the hippocampal response to fluoxetine, which may help refine therapeutic strategies to alleviate depressive disorders.
Translational psychiatry. 01/2011; 1:e56.
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C Vidal,
C Herzog,
A M Haeberle,
C Bombarde,
M C Miquel,
J Carimalo, J M Launay,
S Mouillet-Richard,
C Lasmézas,
D Dormont,
O Kellermann,
Y Bailly
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ABSTRACT: The hypothesis of an early vulnerability of the serotonergic system to prion infection was investigated in a murine model of bovine spongiform encephalopathy (BSE). Behavioral tests targeted to 5-HT functions were performed in the course of infection to evaluate circadian activity, anxiety-like behavior, pain sensitivity and the 5-HT syndrome. The first behavioral change was a decrease in nocturnal activity detected at 30% of incubation time. Further behavioral alterations including nocturnal hyperactivity, reduced anxiety, hyperalgesia and exaggerated 5-HT syndrome were observed at 60%-70% of incubation time, before the onset of clinical signs. The same tests performed in 5-HT-depleted mice and in prion protein-deficient mice revealed behavioral abnormalities similar in many aspects to those of BSE-infected mice. Histological and biochemical analysis showed alterations of the serotonergic system in BSE-infected and prion protein-deficient mice. These results indicate that BSE infection affects the homeostasis of serotonergic neurons and suggest that the disruption of prion protein normal function contributes to the early pathological changes in our mouse model of BSE. A similar process may occur in the human variant Creutzfeldt-Jacob disease, as suggested by the early symptoms of alterations in mood, sleep and pain sensitivity.
Neuroscience 04/2009; 160(4):731-43. · 3.38 Impact Factor
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A Fabre,
J Marchal-Sommé,
S Marchand-Adam,
C Quesnel,
R Borie,
M Dehoux,
C Ruffié,
J Callebert, J-M Launay,
D Hénin,
P Soler,
B Crestani
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ABSTRACT: Serotonin (5-hydroxytryptamine; 5-HT) is known to increase proliferation and collagen synthesis by fibroblasts. Two receptor subtypes, 5-HT2A and 5-HT2B, have been shown to play the most important roles in the lung. In the present study, the role of serotonin in lung fibrosis was investigated using the bleomycin mouse model. Serotonin concentrations in lung homogenates increased significantly over the time course of bleomycin-induced fibrosis, with a maximum at day seven. The expression of serotonin receptors 5-HT2A and 5-HT2B increased in the lung after bleomycin treatment, as assessed by PCR, specific binding and immunohistochemistry. Blockage of 5-HT2A receptors by ketanserin and 5-HT2B receptors by SB215505 reduced bleomycin-induced lung fibrosis, as demonstrated by reduced lung collagen content and reduced procollagen 1 and procollagen 3 mRNA expression. Serotonin antagonists promoted an antifibrotic environment by decreasing the lung mRNA levels of transforming growth factor-beta1, connective growth factor and plasminogen activator inhibitor-1 mRNA, but had minimal effects on lung inflammation as assessed by bronchoalveolar lavage cytology analysis. Interestingly, the 5-HT2B receptor was strongly expressed by fibroblasts in the fibroblastic foci in human idiopathic pulmonary fibrosis samples. In conclusion, the present study showed involvement of serotonin in the pathophysiology of bleomycin-induced lung fibrosis in mice and identified it as a potential therapeutic target in lung fibrotic disorders.
European Respiratory Journal 04/2008; 32(2):426-36. · 5.89 Impact Factor
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ABSTRACT: The monoamine serotonin (5-HT), a well-known neurotransmitter, is also important in peripheral tissues. Several studies have suggested that 5-HT is involved in bone metabolism. Starting from our original observation of increased 5-HT(2B) receptor (5-HT(2B)R) expression during in vitro osteoblast differentiation, we investigated a putative bone phenotype in vivo in 5-HT(2B)R knockout mice. Of interest, 5-HT(2B)R mutant female mice displayed reduced bone density that was significant from age 4 months and had intensified by 12 and 18 months. This histomorphometrically confirmed osteopenia seems to be due to reduced bone formation because 1) the alkaline phosphatase-positive colony-forming unit capacity of bone marrow precursors was markedly reduced in the 5-HT(2B)R mutant mice from 4 to 12 months of age, 2) ex vivo primary osteoblasts from mutant mice exhibited reduced proliferation and delayed differentiation, and 3) calcium incorporation was markedly reduced in osteoblasts after 5-HT(2B)R depletion (produced genetically or by pharmacological inactivation). These findings support the hypothesis that the 5-HT(2B)R receptor facilitates osteoblast recruitment and proliferation and that its absence leads to osteopenia that worsens with age. We show here, for the first time, that the 5-HT(2B)R receptor is a physiological mediator of 5-HT in bone formation and, potentially, in the onset of osteoporosis in aging women.
The FASEB Journal 03/2008; 22(2):418-27. · 5.71 Impact Factor
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ABSTRACT: Serotonin (5-hydroxytryptamine, 5-HT), a monoamine neurotransmitter of the central nervous and peripheral systems (CNS), plays a critical role in a wide variety of physiological and behavioral processes. In the serotonergic system, deregulation of the tightly controlled extracellular concentration of 5-HT appears to be at the origin of a host of metabolic and psychiatric disorders. A key step that regulates 5-HT external level is the re-uptake of 5-HT into cells by the 5-HT transporter (SERT), which is besides the target of numerous drugs interacting with the serotonergic system. Therapeutic strategies have mainly focused on the development of compounds that block the activity of SERT, for instance reuptake inhibitors (e.g. tricyclics, "selective" serotonin reuptake inhibitors) and in the past, specific substrate-type releasers (e.g. amphetamine and cocaine derivatives). Today, generation of new drugs targetting SERT with enhanced selectivity and reduced toxicity is one of the most challenging tasks in drug design. In this context, studies aiming at characterizing the physicochemical properties of 5-HT as well as the biological active conformation of SERT are a prerequisite to the design of new leads. However, the absence of a high-resolution 3D-structure for SERT has hampered the design of new transporter inhibitors. Using computational approaches, numerous efforts were made to shed light on the structure of 5-HT and its transporter. In this review, we compared several in silico methods dedicated to the modeling of 5-HT and SERT with an emphasis on i) quantum chemistry for study of 5-HT conformation and ii) ligand-based (QSAR and pharmacophore models) and transporter-based (homology models) approaches for studying SERT molecule. In addition, we discuss some methodological aspects of the computational work in connection with the construction of putative but reliable 3D structural models of SERT that may help to predict the mechanisms of neurotransmitter transport.
Current Medicinal Chemistry 02/2008; 15(30):3214-27. · 4.86 Impact Factor
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ABSTRACT: Serotonin (5-HT) not only works as a neurotransmitter in the nervous system, but also as a morphogenetic factor during early embryogenesis. In Drosophila, a previous report showed that embryos that lack the 5-HT(2Dro) receptor locus, display abnormal gastrulation movements. In this work, we screened for point mutations in the 5-HT(2Dro) receptor gene. We identified one point mutation that generates a gain of serotonin affinity for the receptor and affects germband extension: 5-HT(2Dro) (C1644). Embryos homozygous for this point mutation display a fourfold increase in the maximal speed of ectodermal cell movements during the rapid phase of germband extension. Homozygous 5-HT(2Dro) (C1644) embryos present a cuticular phenotype, including a total lack of denticle belt. Identification of this gain of function mutation shows the participation of serotonin in the regulation of the cell speed movements during the germband extension and suggests a role of serotonin in the regulation of cuticular formation during early embryogenesis.
Developmental Dynamics 05/2007; 236(4):991-9. · 2.54 Impact Factor
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Developmental Dynamics - DEVELOP DYNAM. 01/2007; 236(4):991-999.
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ABSTRACT: A correlation between high plasma serotonin levels and total pulmonary resistance was reported in more than 80% of pulmonary hypertensive patients. When submitted to chronic hypoxia (10% O(2) for more than 3 weeks), wild-type mice develop lung vascular remodeling and pulmonary hypertension. We previously reported that, in contrast, the development of these hypoxia-dependent alterations is totally abolished in mice with permanent (genetic) or transient (pharmacologic) inactivation of the serotonin 5-hydroxytryptamine (5-HT)(2B) receptor. In the present study, we asked whether 5-HT(2B) receptors could be involved in the control of plasma serotonin levels. Further investigating the chronic hypoxic mouse model of pulmonary hypertension, we first show that in wild-type mice, plasma serotonin levels and 5-HT(2B) receptors expression were significantly increased after chronic exposure to hypoxia. This increase appeared before significant changes in remodeling factors could be detected and persisted when the pathology was established. Conversely, in mice with either genetically or pharmacologically inactive 5-HT(2B) receptors, plasma serotonin levels were not modified by chronic hypoxia. We then confirmed that 5-HT(2B) receptors can control plasma serotonin levels by providing in vivo evidence that an acute agonist stimulation of 5-HT(2B) receptor triggers a transient increase in plasma serotonin that is serotonin transporter dependent and blocked by 5-HT(2B) receptor-selective antagonist or genetic ablation. Our data support the notion that a 5-HT(2B) receptor-dependent regulation of serotonin uptake is implicated in the control of plasma serotonin levels.
Journal of Pharmacology and Experimental Therapeutics 06/2006; 317(2):724-31. · 3.83 Impact Factor
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ABSTRACT: During development, antagonists of 5-HT(2) receptor subtypes cause morphological defects of mesodermal and neural crest derivatives including the craniofacial skeleton. We used an inducible mesoblastic cell line, C1, able to fully convert into osteocytes within 12 days, to assess the involvement of 5-HT(2) receptors during osteogenic differentiation. On day 5 of the osteogenic program, immediately before matrix mineralization, the cells selectively implement 5-HT(2B) receptors (5-HT(2B)R) which remain functional until terminal differentiation. In 5-HT-depleted medium, the receptor exhibits a constitutive activity leading to basal nitric oxide (NO) release and phospholipase A2 (PLA2)-dependent arachidonic acid (AA) production. Blockade of this intrinsic activity affects the efficiency of mineralization by decreasing calcium incorporation within the matrix by 40%. Optimal bone matrix mineralization involves both NO and PLA2 signaling pathways. Moreover, between day 5 and day 10, at the beginning of mineral deposition, the 5-HT(2B)R promotes prostaglandin E2 production through AA-dependent cyclooxygenase (COX) activation. From day 10 onwards, when C1 osteoblasts undergo conversion into osteocyte-like cells, COX activity is quenched. Altogether these observations indicate that the 5-HT(2B)R contributes in an autocrine manner to osteogenic differentiation and highlight a switch in the downstream targets of the receptor at the terminal stage of the program. Finally, in addition to its autocrine function, the 5-HT(2B)R responds to 5-HT by increasing NO production and AA release. These findings raise concern regarding the use of 5-HT(2B)R-related drugs that may interfere with bone metabolism in physiological or pathological situations.
Cellular Signalling 06/2006; 18(5):628-39. · 4.06 Impact Factor
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ABSTRACT: 5-HT2B receptors, in addition to phospholipase C stimulation, are able to trigger activation of the proto-oncogene product p21ras. During mouse embryogenesis, a peak of 5-HT2B receptor expression is detected at the neurulation stage; we localized the 5-HT2B expression in neural crest cells, heart myocardium, and somites. The requirement for functional 5-HT2B receptors shortly after gastrulation, is supported by culture of embryos exposed to 5-HT2B-high affinity antagonist such as ritanserin, which induces morphological defects in the cephalic region, heart and neural tube.Functional 5-HT2B receptors are also expressed during the serotonergic differentiation of the mouse F9 teratocarcinoma-derived clonal cell line 1C11. Upon 2 days of induction by cAMP, 5-HT2B receptors become functional, and on day 4, the appearance of 5-HT2A receptors coincides with the onset of active serotonin transporter by these cells. Active serotonin uptake is modulated by serotonin suggesting autoreceptor functions for 5-HT2B receptors.
Annals of the New York Academy of Sciences 02/2006; 861(1):67 - 73. · 3.15 Impact Factor
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M-M Rodriguez,
K Peoc'h,
S Haïk,
C Bouchet,
L Vernengo,
G Mañana,
R Salamano,
L Carrasco,
M Lenne,
P Beaudry, J-M Launay,
J-L Laplanche
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ABSTRACT: Inherited prion diseases are characterized by mutations in the PRNP gene encoding the prion protein (PrP). We report a novel missense mutation in the PRNP gene (resulting in a G114V mutation in PrP) in members of a Uruguayan family with clinical and histopathologic features of prion disease. Affected individuals were characterized by an early age at onset, initial neuropsychiatric symptoms, late dementia with prominent pyramidal and extrapyramidal symptoms, and long disease duration.
Neurology 05/2005; 64(8):1455-7. · 8.31 Impact Factor
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ABSTRACT: The serotonergic system plays a critical role in a wide variety of physiological and behavioral processes. Dysregulation of the tightly controlled extracellular concentration of serotonin (5-hydroxytryptamine, 5-HT) appears to be at the origin of a host of metabolic and psychiatric disorders. Since the plasma membrane 5-HT transporter (SERT) is the major protagonist in regulating extracellular 5-HT concentration, SERT is the target of most drugs interacting with the serotonergic system. Unfortunately, some of the drugs towards SERT (e.g. amphetamine derivatives) interfere with cell homeostasis leading to cell toxicity. Developing new SERT ligands devoid of any side-effect represents a major priority in the treatment of 5-HT-associated pathologies. Here, we report structure-activity relationships (SAR) and three-dimensional QSAR (3D-QSAR) studies of a library of 121 compounds including 5-HT analogs, harmanes, benzothiazoles, indanones, amphetamine derivatives and substrate-type 5-HT releasers, with the goal of identifying the structural determinants crucial for SERT uptake. In the absence of data about the bioactive form of 5-HT, conformational analysis of 5-HT was performed using quantum chemistry calculations. This led to three 5-HT stable conformers with anti, -gauche and +gauche side-chain conformation. These conformers, used as templates for superimposition with all the library compounds, enabled the design of a reliable 6-points pharmacophore representative of SERT uptake activity. Molecular dynamics (MD) simulations performed with compounds that are efficiently, moderately, poorly or not transported by SERT allowed to assess the validity of our pharmacophore. Altogether, our data provide for the first time a reliable pharmacophore of SERT uptake activity, which may help to the design of new drugs targeting SERT.
Current Medicinal Chemistry 02/2005; 12(20):2393-410. · 4.86 Impact Factor
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J-M Launay,
P Hervé,
K Peoc'h,
C Tournois,
J Callebert,
C G Nebigil,
N Etienne,
L Drouet,
M Humbert,
G Simonneau,
L Maroteaux
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ABSTRACT: Primary pulmonary hypertension is a progressive and often fatal disorder in humans that results from an increase in pulmonary blood pressure associated with abnormal vascular proliferation. Dexfenfluramine increases the risk of pulmonary hypertension in humans, and its active metabolite is a selective serotonin 5-hydroxytryptamine 2B (5-HT(2B)) receptor agonist. Thus, we investigated the contribution of the 5-HT(2B)receptor to the pathogenesis of pulmonary hypertension. Using the chronic-hypoxic-mouse model of pulmonary hypertension, we found that the hypoxia-dependent increase in pulmonary blood pressure and lung remodeling are associated with an increase in vascular proliferation, elastase activity and transforming growth factor-beta levels, and that these parameters are potentiated by dexfenfluramine treatment. In contrast, hypoxic mice with genetically or pharmacologically inactive 5-HT(2B)receptors manifested no change in any of these parameters. In both humans and mice, pulmonary hypertension is associated with a substantial increase in 5-HT(2B) receptor expression in pulmonary arteries. These data show that activation of 5-HT(2B) receptors is a limiting step in the development of pulmonary hypertension.
Nature Medicine 11/2002; 8(10):1129-35. · 22.46 Impact Factor
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M Humbert,
P Labrune,
O Sitbon,
C Le Gall,
J Callebert,
P Hervé,
D Samuel,
R Machado,
R Trembath,
L Drouet, J M Launay,
G Simonneau
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ABSTRACT: A case of pulmonary arterial hypertension in a patient with type-Ia glycogen-storage disease, a rare autosomal recessive disorder caused by a deficiency of glucose-6-phosphatase is reported in this study. It has been suggested that the occurrence of pulmonary arterial hypertension in type-Ia glycogen-storage disease could be due to an abnormal production of vasoconstrictive amines such as serotonin. To test this hypothesis, plasma serotonin concentrations were prospectively measured in 13 patients with type-Ia glycogen-storage disease, one patient with severe pulmonary hypertension and type-Ia glycogen-storage disease, 16 patients displaying severe pulmonary arterial hypertension, and 26 normal healthy controls. Elevated plasma serotonin concentrations were found in patients with either severe pulmonary arterial hypertension (38.8+/-7.3 nmol x L(-1)) or type-Ia glycogen-storage disease (36.8+/-11.5 nmol x L(-1)), as compared with controls (8.8+/-0.6 nmol x L(-1), p<0.001). Plasma serotonin was dramatically elevated in the patient with type-Ia glycogen-storage disease and pulmonary arterial hypertension (113.4 nmol x L(-1)). It is concluded that type-Ia glycogen-storage disease may be another condition in which abnormal handling of serotonin is one event in a multistep process leading to severe pulmonary arterial hypertension.
European Respiratory Journal 07/2002; 20(1):59-65. · 5.89 Impact Factor
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C Betancur,
M Corbex,
C Spielewoy,
A Philippe,
J L Laplanche, J M Launay,
C Gillberg,
M C Mouren-Siméoni,
M Hamon,
B Giros,
M Nosten-Bertrand,
M Leboyer
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ABSTRACT: Previous studies have provided conflicting evidence regarding the association of the serotonin transporter (5-HTT) gene with autism. Two polymorphisms have been identified in the human 5-HTT gene, a VNTR in intron 2 and a functional deletion/insertion in the promoter region (5-HTTLPR) with short and long variants. Positive associations of the 5-HTTLPR polymorphism with autism have been reported by two family-based studies, but one found preferential transmission of the short allele and the other of the long allele. Two subsequent studies failed to find evidence of transmission disequilibrium at the 5-HTTLPR locus. These conflicting results could be due to heterogeneity of clinical samples with regard to serotonin (5-HT) blood levels, which have been found to be elevated in some autistic subjects. Thus, we examined the association of the 5-HTTLPR and VNTR polymorphisms of the 5-HTT gene with autism, and we investigated the relationship between 5-HTT variants and whole-blood 5-HT. The transmission/disequilibrium test (TDT) revealed no linkage disequilibrium at either loci in a sample of 96 families comprising 43 trios and 53 sib pairs. Furthermore, no significant relationship between 5-HT blood levels and 5-HTT gene polymorphisms was found. Our results suggest that the 5-HTT gene is unlikely to play a major role as a susceptibility factor in autism.
Molecular Psychiatry 02/2002; 7(1):67-71. · 13.67 Impact Factor
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Journal of Neurochemistry - J NEUROCHEM. 01/2002; 82(3):615-624.
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P Quintin,
C Benkelfat, J M Launay,
I Arnulf,
A Pointereau-Bellenger,
S Barbault,
J C Alvarez,
O Varoquaux,
F Perez-Diaz,
R Jouvent,
M Leboyer
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ABSTRACT: The lowering of mood induced by an acute tryptophan depletion (ATD) has been proposed as a candidate endophenotype for the vulnerability to manic-depressive illness. This study tests this hypothesis in relatives of probands from well-characterized multiplex families affected with bipolar affective disorder (BAD).
In a double-blind, crossover design, 20 unaffected relatives (URs) and 19 control subjects received either a 100-g amino acid (AA) drink devoid of tryptophan or a placebo, respectively. Clinical and biochemical effects of ATD were compared between unaffected relatives of BAD probands and age- and sex-matched control subjects.
At 5 hours after AA drink ingestion, relative to the placebo, ATD resulted in 74% and 84% decreases in total plasma tryptophan concentrations in control subjects and relatives of patients with BAD, respectively. Unlike control subjects unaffected relatives experienced a lowering of mood during ATD but not with the placebo. Furthermore, URs tended to show increased impulsivity in the ATD condition. Measurements obtained before ingestion of the AA drink indicated that, relative to control subjects URs exhibited lower serotonin platelet concentrations, lower affinity, and fewer binding sites of the serotonin transporter for imipramine; these differences were unaffected by ATD.
These results replicate and extend previous findings suggesting that URs of patients with BAD are more susceptible to low tryptophan availability. This finding may bear significance in the purported role of serotonergic mechanisms in the vulnerability to depressive syndrome and/or illness.
Biological Psychiatry 09/2001; 50(3):184-90. · 8.28 Impact Factor
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ABSTRACT: Serotonin (5-hydroxytryptamine, 5-HT) binds to numerous cognate receptors to initiate its biological effects. In this review, we have focused on the 5-HT2B receptor to address how signaling and expression of this receptor is specifically implicated in embryonic development and adult health and disease. Transduction of the 5-HT2B signaling is complex, including phospholipase C and A2 stimulation, cGMP production and a mitogenic signal that integrates the tyrosine kinase-signaling pathway. Furthermore, 5-HT, through the 5-HT2B receptors, has the ability to control serotonergic differentiation of committed neuron-like cells. In addition, 5-HT2B receptors are actively involved in the transient action of 5-HT during embryonic morphogenesis. Our recent data presented the first genetic evidence that 5-HT via 5-HT2B receptors regulates cardiac embryonic development and adult functions and suggested that this receptor subtype may be involved in other physiopathological situations. In particular, 5-HT-dependent molecular mechanisms may be involved in embryonic development and postnatal maturation of the enteric nervous system. Also, the involvement of the 5-HT2B receptor in the vascular growth often observed in hypertension is likely. These probably result from reactivation of developmentally regulated receptors in pathological situations. Finally, embryonic functions of 5-HT2 receptors observed in Drosophila gastrulation suggest evolutionary conserved mechanisms.
International Journal of Developmental Neuroscience 08/2001; 19(4):365-72. · 2.42 Impact Factor
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C G Nebigil,
P Hickel,
N Messaddeq,
J L Vonesch,
M P Douchet,
L Monassier,
K György,
R Matz,
R Andriantsitohaina,
P Manivet, J M Launay,
L Maroteaux
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ABSTRACT: Identification of factors regulating myocardial structure and function is important to understand the pathogenesis of heart disease. Because little is known about the molecular mechanism of cardiac functions triggered by serotonin, the link between downstream signaling circuitry of its receptors and the heart physiology is of widespread interest. None of the serotonin receptor (5-HT(1A), 5-HT(1B), or 5-HT(2C)) disruptions in mice have resulted in cardiovascular defects. In this study, we examined 5-HT(2B) receptor-mutant mice to assess the putative role of serotonin in heart structure and function.
We have generated G(q)-coupled 5-HT(2B) receptor-null mice by homologous recombination. Surviving 5-HT(2B) receptor-mutant mice exhibit cardiomyopathy with a loss of ventricular mass due to a reduction in number and size of cardiomyocytes. This phenotype is intrinsic to cardiac myocytes. 5-HT(2B) receptor-mutant ventricles exhibit dilation and abnormal organization of contractile elements, including Z-stripe enlargement and N-cadherin downregulation. Echocardiography and ECG both confirm the presence of left ventricular dilatation and decreased systolic function in the adult 5-HT(2B) receptor-mutant mice.
Mutation of 5-HT(2B) receptor leads to a cardiomyopathy without hypertrophy and a disruption of intercalated disks. 5-HT(2B) receptor is required for cytoskeleton assembly to membrane structures by its regulation of N-cadherin expression. These results constitute, for the first time, strong genetic evidence that serotonin, via the 5-HT(2B) receptor, regulates cardiac structure and function.
Circulation 07/2001; 103(24):2973-9. · 14.74 Impact Factor
