Tissue homeostasis requires an effective, limited wound-healing response to injury. In chronic disease, failure to regenerate parenchymal tissue leads to the replacement of lost cellular mass with a ...fibrotic matrix. The mechanisms that dictate the balance of cell regeneration and fibrogenesis are not well understood. Here we report that fibrogenic hepatic stellate cells (HSCs) in the liver are negative regulators of hepatocyte regeneration. This negative regulatory function requires stimulation of the 5-hydroxytryptamine 2B receptor (5-HT(2B)) on HSCs by serotonin, which activates expression of transforming growth factor β1 (TGF-β1), a powerful suppressor of hepatocyte proliferation, through signaling by mitogen-activated protein kinase 1 (ERK) and the transcription factor JunD. Selective antagonism of 5-HT(2B) enhanced hepatocyte growth in models of acute and chronic liver injury. We also observed similar effects in mice lacking 5-HT(2B) or JunD or upon selective depletion of HSCs in wild-type mice. Antagonism of 5-HT(2B) attenuated fibrogenesis and improved liver function in disease models in which fibrosis was pre-established and progressive. Pharmacological targeting of 5-HT(2B) is clinically safe in humans and may be therapeutic in chronic liver disease.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Addiction is a maladaptive pattern of behavior following repeated use of reinforcing drugs in predisposed individuals, leading to lifelong changes. Common among these changes are alterations of ...neurons releasing dopamine in the ventral and dorsal territories of the striatum. The serotonin 5-HT
receptor has been involved in various behaviors, including impulsivity, response to antidepressants, and response to psychostimulants, pointing toward putative interactions with the dopamine system. Despite these findings, it remains unknown whether 5-HT
receptors directly modulate dopaminergic activity and the possible mechanisms involved. To answer these questions, we investigated the contribution of 5-HT
receptors to cocaine-dependent behavioral responses. Male mice permanently lacking 5-HT
receptors, even restricted to dopamine neurons, developed heightened cocaine-induced locomotor responses. Retrograde tracing combined with single-cell mRNA amplification indicated that 5-HT
receptors are expressed by mesolimbic dopamine neurons.
and
electrophysiological recordings showed that 5-HT
-receptor inactivation in dopamine neurons affects their neuronal activity and increases AMPA-mediated over NMDA-mediated excitatory synaptic currents. These changes are associated with lower ventral striatum dopamine activity and blunted cocaine self-administration. These data identify the 5-HT
receptor as a pharmacological intermediate and provide mechanistic insight into attenuated dopamine tone following exposure to drugs of abuse.
Here we report that mice lacking 5-HT
receptors totally or exclusively in dopamine neurons exhibit heightened cocaine-induced locomotor responses. Despite the sensitized state of these mice, we found that associated changes include lower ventral striatum dopamine activity and lower cocaine operant self-administration. We described the selective expression of 5-HT
receptors in a subpopulation of dopamine neurons sending axons to the ventral striatum. Increased bursting
properties of these dopamine neurons and a concomitant increase in AMPA synaptic transmission to
dopamine neurons were found in mice lacking 5-HT
receptors. These data support the idea that the chronic 5-HT
-receptor inhibition makes mice behave like animals already exposed to cocaine with higher cocaine-induced locomotion associated with changes in dopamine neuron reactivity.
Pulmonary arterial hypertension (PAH) is a progressive disease characterized by lung endothelial dysfunction and vascular remodeling. Recently, bone marrow progenitor cells have been localized to PAH ...lungs, raising the question of their role in disease progression. Independently, serotonin (5-HT) and its receptors have been identified as contributors to the PAH pathogenesis. We hypothesized that 1 of these receptors, 5-HT2B, is involved in bone marrow stem cell mobilization that participates in the development of PAH and pulmonary vascular remodeling. A first study revealed expression of 5-HT2B receptors by circulating c-kit+ precursor cells, whereas mice lacking 5-HT2B receptors showed alterations in platelets and monocyte-macrophage numbers, and in myeloid lineages of bone marrow. Strikingly, mice with restricted expression of 5-HT2B receptors in bone marrow cells developed hypoxia or monocrotaline-induced increase in pulmonary pressure and vascular remodeling, whereas restricted elimination of 5-HT2B receptors on bone marrow cells confers a complete resistance. Moreover, ex vivo culture of human CD34+ or mice c-kit+ progenitor cells in the presence of a 5-HT2B receptor antagonist resulted in altered myeloid differentiation potential. Thus, we demonstrate that activation of 5-HT2B receptors on bone marrow lineage progenitors is critical for the development of PAH.
Serotonin (5-HT) transporter (SERT) regulates the level of 5-HT in placenta. Initially, we found that in gestational diabetes mellitus (GDM), whereas free plasma 5-HT levels were elevated, the 5-HT ...uptake rates of trophoblast were significantly down-regulated, due to impairment in the translocation of SERT molecules to the cell surface. We sought to determine the factors mediating the down-regulation of SERT in GDM trophoblast. We previously reported that an endoplasmic reticulum chaperone, ERp44, binds to Cys200 and Cys209 residues of SERT to build a disulfide bond. Following this posttranslational modification, before trafficking to the plasma membrane, SERT must be dissociated from ERp44; and this process is facilitated by insulin signaling and reversed by the insulin receptor blocker AGL2263. However, the GDM-associated defect in insulin signaling hampers the dissociation of ERp44 from SERT. Furthermore, whereas ERp44 constitutively occupies Cys200/Cys209 residues, one of the SERT glycosylation sites, Asp208 located between the two Cys residues, cannot undergo proper glycosylation, which plays an important role in the uptake efficiency of SERT. Herein, we show that the decrease in 5-HT uptake rates of GDM trophoblast is the consequence of defective insulin signaling, which entraps SERT with ERp44 and impairs its glycosylation. In this regard, restoring the normal expression of SERT on the trophoblast surface may represent a novel approach to alleviating some GDM-associated complications.
Significance Our findings provide insight on the molecular mechanism in which insulin regulates the dissociation of ERp44, an endoplasmic reticulum chaperon, from the serotonin (5-HT) transporter (SERT) following the completion of disulfide bond formation. Furthermore, our data show that gestational diabetes mellitus-associated defects in insulin signaling tethers SERT with ERp44, at the intracellular compartment which down-regulates 5-HT uptake rates of the placental trophoblast. All the trophoblast used in these studies were isolated and purified directly from healthy or GDM placentas in our laboratories.
Transient reduced food intake (hypophagia) following high stress could have beneficial effects on longevity, but paradoxically, hypophagia can persist and become anorexia-like behavior. The neural ...underpinnings of stress-induced hypophagia and the mechanisms by which the brain prevents the transition from transient to persistent hypophagia remain undetermined. In this study, we report the involvement of a network governing goal-directed behavior (decision). This network consists of the ascending serotonergic inputs from the dorsal raphe nucleus (DR) to the medial prefrontal cortex (mPFC). Specifically, adult restoration of serotonin 4 receptor (5-HT4R) expression in the mPFC rescues hypophagia and specific molecular changes related to depression resistance in the DR (5-HT release elevation, 5-HT1A receptor, and 5-HT transporter reductions) of stressed 5-HT4R knockout mice. The adult mPFC-5-HT4R knockdown mimics the null phenotypes. When mPFC-5-HT4Rs are overexpressed and DR-5-HT1ARs are blocked in the DR, hypophagia following stress persists, suggesting an antidepressant action of early anorexia.
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•mPFC-5-HT4Rs are causally linked to hypophagia following stress•mPFC-5-HT4Rs mediate stress-induced changes in DR-5-HT parameters•mPFC-5-HT4Rs are counterbalanced by DR-5-HT1A to prevent early anorexia•Hypophagia due to stress does not occur in early stages of development
Jean et al. report causal relationships between serotonin 4 receptors and stress-induced hypophagia, attributable to specific neural signals of depression resistance in the dorsal raphe nucleus, which protect from early anorexia.
Tryptophan as the precursor of several active compounds, including kynurenine and serotonin, is critical for numerous important metabolic functions. Enhanced tryptophan metabolism toward the ...kynurenine pathway has been associated with myelodysplastic syndromes (MDSs), which are preleukemic clonal diseases characterized by dysplastic bone marrow and cytopenias. Here, we reveal a fundamental role for tryptophan metabolized along the serotonin pathway in normal erythropoiesis and in the physiopathology of MDS-related anemia. We identify, both in human and murine erythroid progenitors, a functional cell-autonomous serotonergic network with pro-survival and proliferative functions. In vivo studies demonstrate that pharmacological increase of serotonin levels using fluoxetine, a common antidepressant, has the potential to become an important therapeutic strategy in low-risk MDS anemia refractory to erythropoietin.
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•In mouse, bone-marrow-derived serotonin (5-HT) contributes to normal erythropoiesis•Serotonin-deficient mice exhibit anemia and an MDS-like phenotype•Lack of 5-HT decreases proliferation and survival of human erythroid progenitors•Pharmacologic restoration of 5-HT can rescue anemia, whether MDS related or not
Sibon et al. identify a cell-autonomous serotonergic network in human and mouse erythroid progenitors. Reduced levels of serotonin lead to decreased proliferation and survival of erythroid progenitors. Increasing serotonin’s concentration through fluoxetine, commonly used to treat depression, could be a valuable therapeutic intervention to correct myelodysplastic-syndrome-related anemia.
The amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) reverses dopamine and serotonin transporters to produce efflux of dopamine and serotonin, respectively, in regions of the ...brain that have been implicated in reward. However, the role of serotonin/dopamine interactions in the behavioral effects of MDMA remains unclear. We previously showed that MDMA-induced locomotion, serotonin and dopamine release are 5-HT(2B) receptor-dependent. The aim of the present study was to determine the contribution of serotonin and 5-HT(2B) receptors to the reinforcing properties of MDMA.We show here that 5-HT(2B) (-/-) mice do not exhibit behavioral sensitization or conditioned place preference following MDMA (10 mg/kg) injections. In addition, MDMA-induced reinstatement of conditioned place preference after extinction and locomotor sensitization development are each abolished by a 5-HT(2B) receptor antagonist (RS127445) in wild type mice. Accordingly, MDMA-induced dopamine D1 receptor-dependent phosphorylation of extracellular regulated kinase in nucleus accumbens is abolished in mice lacking functional 5-HT(2B) receptors. Nevertheless, high doses (30 mg/kg) of MDMA induce dopamine-dependent but serotonin and 5-HT(2B) receptor-independent behavioral effects.These results underpin the importance of 5-HT(2B) receptors in the reinforcing properties of MDMA and illustrate the importance of dose-dependent effects of MDMA on serotonin/dopamine interactions.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Serotonin (5-HT) is a multifunctional signaling molecule that plays different roles in a concentration-dependent manner. We demonstrated that elevated levels of plasma 5-HT accelerate platelet ...aggregation resulting in a hypercoagulable state in which the platelet surface becomes occupied by several glycoproteins. Here we study the novel hypothesis that an elevated level of plasma 5-HT results in modification of the content of N-glycans on the platelet surface and this abnormality is associated with platelet aggregation. Mass spectrometry of total surface glycoproteins on platelets isolated from wild-type mice infused for 24 hours with saline or 5-HT revealed that the content of glycoproteins on platelets from 5-HT-infused mice switched from predominantly N-acetyl-neuraminic acid (Neu5Ac) to N-glycolyl-neuraminic acid (Neu5Gc). Cytidine monophosphate-N-acetylneuraminate hydroxylase (CMAH) synthesizes Neu5Gc from Neu5Ac. Up-regulation of Neu5Gc content on the platelet surface resulted from an increase in the catalytic function, not expression, of CMAH in platelets of 5-HT-infused mice. The highest level of Neu5Gc was observed in platelets of 5-HT-infused, 5-HT transporter-knock out mice, suggesting that the surface delineated 5-HT receptor on platelets may promote CMAH catalytic activity. These new findings link elevated levels of plasma 5-HT to altered platelet N-glycan content, a previously unrecognized abnormality that may favor platelet aggregation.
Objectives
Although critical in animal and human development and pathology, a measurement of the quantitative expression of 5-HTR serotonin receptors on animal or human valvular tissues has never ...been performed.
Methods
Quantification of the most frequent 5-HTRs reported as being present in human peripheral tissue was performed using radiolabeled agonists/antagonists. A membrane protein extract from normal human valves (aortic/mitral/tricuspid and some pulmonary) and associated diseased left myocardium, all unusable in clinics, were obtained from the Homograft bank.
Results
We analyzed 5-HT
1A
R/5-HT
1B/D
R/5-HT
2A
R/5-HT
2B
R/5-HT
2C
R/5-HT
4
R/5-HT
7
R from 28 hearts. We confirmed the presence of tissue and measured the quantitative content for respective proteins in femtomol/mg of protein extracts: for 5-HT
2A
R (35.9+/−0.7), 5-HT
2B
R (28.8+/−1.3) but also a newly observed and robust expression for 5-HT
4
R (38+/−4.2). We identified one, 5-HT
1A
Rs (4.9+/−0.3), and the possible expression, but at a very low level, of previously reported 5-HT
1B/D
Rs (1.3+/−0.5) as well as the new 5-HT
7
Rs (3.5+/0.1) and 5-HT
2C
Rs (1.2+/−0.1). Interestingly, by using univariate analysis, we were able to observe many correlations between the different 5-HTR levels of expression especially between 5-HT
1A
R/5-HT
1B/D
R and also between 5-HT
4
R/5-HT
7
R, but none were observed between 5-HT
2A
R and 5-HT
2B
R. Using multivariate analyses for a specific 5-HTR level of expression, after adjustment for implantation sites and other 5-HTRs, we found that 5-HT
1A
R was correlated with 5-HT
1B/D
R;5-HT
4
R with 5-HT
7
R and 5-HT
1A
R;5-HT
2B
R with 5-HT
2A
R only. For 5-HT
2
C, no correlation was observed.
Conclusion
5-HT
2A
R/5-HT
2B
R and 5-HT
4
R were all observed to have a high and equal level of expression on human valves, but that of 5-HT
1A
R was more limited. Since these non-5-HT
2
Rs are coupled with different G-proteins, with specific signaling, theoretically they may control the main 5-HT
2
R signaling (i.e., PLC/DAG-PKC-ERK/Ras/Src signaling) involved in valvular fibrosis and degeneration.
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