Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The neuromodulator systems mediating the central component of the hypoxic ventilatory response (HVR) during development are complex and diverse. The early component of the HVR is mediated through N-methyl-D-aspartate (NMDA) glutamate receptors in the caudal brainstem. The intracellular downstream signal transductions of the NMDA receptors involve protein kinase C (PKC), neuronal nitric oxide synthase (nNOS) and tyrosine kinase (TK). Activation of NMDA receptors will also lead to activation of the early gene transcription factors including AP-1 (c-fos, c-jun) and NF-kappaB which may play a role in modulation of the subsequent response to hypoxia. NMDA receptors in the caudal brainstem play a critical role in the development of the HVR and increasing dependency on NMDA receptors emerges over time. Similarly, hypoxia-induced PKC, NOS and c-Fos activation in the caudal brainstem is relatively weak in the immature animals, but this activation increases with age and the strength of the response appears to increase concomitantly with the appearance of NMDA expression. Several neurotransmitters including adenosine, gamma-aminobutyric acid (GABA), serotonin and opioids are involved in the late component of the HVR. In addition, the late phase of the HVR is mediated in part through platelet-derived growth factor (PDGF)-beta receptors. PDGF-beta receptor activation is an important contributor of the hypoxic ventilatory depression at all postnatal ages, but its role is more critical in the developing animals. Maturation of these neuromodulators, especially the NMDA and PDGF-beta receptors-mediated pathways, occurs primarily during the early postnatal period. Perturbation of these developmental processes may result in short-term or sustained alterations to the HVR and may also affect neuronal survival during hypoxia.
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PMID:Maturational changes in neuromodulation of central pathways underlying hypoxic ventilatory response. 1595 May 54

N-methyl-D-aspartate (NMDA)-type glutamate receptors perform critical functions during the development of the nervous system and in the initiation of synaptic plasticity. An important mechanism in setting the gain of NMDA receptors involves the stimulation of G-protein-coupled receptors (GPCRs), which through activation of protein tyrosine kinases leads to an upregulation of NMDA receptors. In contrast, little is known about how NMDA receptors are downregulated. In the present study, we characterized a signaling pathway that mediates the depression of NMDA receptor function in response to stimulation of muscarinic acetylcholine receptors. Whole-cell patch-clamp recordings obtained from CA3 pyramidal cells in organotypic slice cultures revealed that under conditions of low intracellular calcium buffering application of muscarine-depressed NMDA receptor current. The sensitivity of this response to pirenzipine indicated that the M1 acetylcholine receptor is mediating this depression. The muscarine-induced depression of NMDA current was prevented by blocking G-protein function or after depleting intracellular Ca2+ stores with cyclopiazonic acid. Inhibitors of calmodulin prevented the depression whereas blocking calcineurin enhanced the depression of NMDA currents. Blocking tyrosine phosphatase activity with pervanandate converted the muscarine-induced depression into a potentiation of NMDA currents, whereas blocking protein kinase A (H-89), Src kinase (PP2, SU6656), or PKC (GF 109203X) failed to prevent the depression of NMDA currents. As Src tyrosine kinase is known to phosphorylate and upregulate NMDA receptors, we propose that a protein tyrosine phosphatase(s) counteracting the action of Src is the final target in the mAChR-dependent inhibitory signaling cascade. Our data are consistent with a transduction cascade comprising an M1 acetylcholine receptor-->G-protein-->Ca2+ release-->calmodulin-->tyrosine phosphatase.
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PMID:Muscarinic receptor stimulation reduces NMDA responses in CA3 hippocampal pyramidal cells via Ca2+-dependent activation of tyrosine phosphatase. 1599 5

The neurotrophins-nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), NT-3 and NT-4-represent a family of proteins essential for neuronal survival and plasticity. Each neurotrophin can signal through two different transmembrane receptors, Trk receptor tyrosine kinases and the p75 neurotrophin receptor, the first member of the TNF receptor superfamily. Neurotrophic factors play an important role in neurodegenerative diseases, as well as neuropsychiatric disorders such as depression, bipolar disease and eating disorders. Indeed, a number of approaches have been taken to use neurotrophins to treat Alzheimer's dementia, amyotrophic lateral sclerosis and peripheral sensory neuropathy. However, many of these clinical trails have failed, due to problems in delivery and unforeseen side effects of neurotrophic factors. An alternative approach is to use ligands in the G protein-coupled receptor (GPCR) family to transactivate trophic activities. We have discovered that treatment with adenosine, a neuromodulator that acts through G protein-coupled receptors, is capable of activating Trk tyrosine kinase receptors. Transactivation of neurotrophic receptors by GPCR ligands raise the possibility that small molecules may be used to elicit neurotrophic effects for the treatment of neurodegenerative diseases. This approach would allow for selective targeting of neurons that express specific G protein-coupled receptors and trophic factor receptors. GPCRs transduce information provided by extracellular signals to modulate synaptic activity and neurotransmission. In addition to the classical G protein signalling, GPCR ligands also activate receptor tyrosine kinases (RTK), including neurotrophin receptors. Activation of Trk neurotrophin receptors can occur by GPCR ligands in the absence of neurotrophins. Adenosine and PACAP (pituitary adenylate cyclase activating polypeptide) induce Trk activation specifically through their respective GPCRs to promote cell survival. Transactivation of Trks by GPCRs has emerged as a new theme in the biology of neurotrophin function. Although the precise role of transactivation is unknown, one possibility is that it adds a safety factor that might protect neurons from death in the absence of neurotrophins. Abnormal activity of the neurotrophin system has been implicated in several psychiatric and neurobiological illnesses. However, the lack of knowledge about the precise site of neurotrophin dysfunction has compromised the ability to improve the efficacy and the safety of drugs used in treatment modalities. If small-molecule GPCR ligands can ameliorate neuronal cell loss through Trk, transactivation may offer a new strategy for promoting trophic effects during neurodegeneration.
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PMID:Promoting neurotrophic effects by GPCR ligands. 1680 30

Transient cerebral ischemia causes an inhomogeneous pattern of cell death in the brain. We investigated mechanisms, which may underlie the greater susceptibility of hippocampal CA1 vs. CA3 pyramidal cells to ischemic insult. Using an in vitro oxygen-glucose deprivation (OGD) model of ischemia, we found that N-methyl-D-aspartate (NMDA) responses were enhanced in the more susceptible CA1 pyramidal cells and transiently depressed in the resistant CA3 pyramidal cells. The long-lasting potentiation of NMDA responses in CA1 cells was associated with delayed cell death and was prevented by blocking tyrosine kinase-dependent up-regulation of NMDA receptor function. In CA3 cells, the energy deprivation-induced transient depression of NMDA responses was converted to potentiation by blocking protein phosphatase signalling. These results suggest that energy deprivation differentially shifts the intracellular equilibrium between the tyrosine kinase and phosphatase activities that modulate NMDA responses in CA1 and CA3 pyramidal cells. Therapeutic modulation of tyrosine phosphorylation may thus prove beneficial in mitigating ischemia-induced neuronal death in vulnerable brain areas.
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PMID:NMDA receptors and the differential ischemic vulnerability of hippocampal neurons. 1681 62

The human 5-HT(6) receptor (5-HT(6)R) is one of the latest cloned receptors among the known 5-HT receptors. Its abundant distribution in the limbic region, which participates in the control of mood and emotion and is involved in nervous system diseases such as depression and Alzheimer disease, has caused it to generate much interest. However, the cellular mechanisms of 5-HT(6)R are poorly understood. In the present study we found, using a yeast two-hybrid assay, that the carboxyl-terminal region of 5-HT(6)R interacts with the Fyn-tyrosine kinase. We also determined using a glutathione S-transferase pulldown assay that this interaction was mediated through the SH3 domain of Fyn and confirmed this by co-immunoprecipitation assays in two different transfected cell lines as well as in adult rat brains. Immunocyto(histo)chemistry also showed prominent co-localization between 5-HT(6)R and Fyn in transfected cells and a similar distribution between 5-HT(6)R and Fyn in the rat brain. Based on this interaction, we further examined the modulation of 5-HT(6)R by Fyn and vice versa. In addition, we demonstrated that the activation of 5-HT(6)R activated the extracellular signal-regulated kinase1/2 via an Fyn-dependent pathway. These findings suggest that Fyn may play an important role in 5-HT(6)R- mediated signaling pathways in the central nervous system.
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PMID:The novel cellular mechanism of human 5-HT6 receptor through an interaction with Fyn. 1718 69

The receptor tyrosine kinase product of the anaplastic lymphoma kinase (ALK) gene has been implicated in oncogenesis as a product of several chromosomal translocations, although its endogeneous role in the hematopoietic and neural systems has remained poorly understood. We describe that the generation of animals homozygous for a deletion of the ALK tyrosine kinase domain leads to alterations in adult brain function. Evaluation of adult ALK homozygotes (HOs) revealed an age-dependent increase in basal hippocampal progenitor proliferation and alterations in behavioral tests consistent with a role for this receptor in the adult brain. ALK HO animals displayed an increased struggle time in the tail suspension test and the Porsolt swim test and enhanced performance in a novel object-recognition test. Neurochemical analysis demonstrates an increase in basal dopaminergic signalling selectively within the frontal cortex. Altogether, these results suggest that ALK functions in the adult brain to regulate the function of the frontal cortex and hippocampus and identifies ALK as a new target for psychiatric indications, such as schizophrenia and depression, with an underlying deregulated monoaminergic signalling.
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PMID:Behavioral and neurochemical alterations in mice deficient in anaplastic lymphoma kinase suggest therapeutic potential for psychiatric indications. 1748 25

The 'neurotrophin hypothesis of depression' is based largely on correlations between stress or antidepressant treatment and down- or upregulation, respectively, of brain-derived neurotrophic factor (BDNF). Genetic disruption of the signaling pathways involving BDNF and its receptor, the tyrosine kinase TrkB, does not seem to cause depressive behaviors, but does hamper the effect of antidepressant drugs. Thus, BDNF may be a target of antidepressants, but not the sole mediator of depression or anxiety. Advances in BDNF cell biology, including its transcription through multiple promoters, trafficking and secretion, may provide new insights into its role in mood disorders. Moreover, as the precursor proBDNF and the mature protein mBDNF can elicit opposite effects on cellular functions, the impact of proBDNF and its cleavage on mood should be considered. Opposing influences of mBDNF and proBDNF on long-term potentiation and long-term depression might contribute to the dichotomy of BDNF actions on behaviors mediated by the brain stress and reward systems.
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PMID:New insights into BDNF function in depression and anxiety. 1772 74

The concentration of the cytokine fms-like tyrosine kinase-3 ligand (FL) is elevated in the plasma of patients treated with chemotherapy or radiotherapy for malignant conditions. In addition, plasma FL is increased in patients with bone marrow failure resulting from stem-cell defects (e.g. aplastic anaemia). Our goal in the present study was to measure the concentration of serum FL in mice treated with the chemotherapeutic agent busulphan (BU) to induce bone marrow depression and relate changes in FL to effects on haemopoiesis. Female CD-1 mice were treated with BU (9.0 mg/kg) or vehicle by intraperitoneal injection on 10 occasions over 21 days. Animals were autopsied on days 1, 23, 72, 119 and 177 postdosing. A full blood count was performed, and serum prepared for FL analysis. Femoral marrow cell suspensions were prepared to assess the total femoral nucleated cell count (FNCC) and the number of committed haemopoietic progenitor cells (CFU-C). On days 1 and 23 postdosing, significant decreases were evident in many peripheral blood parameters; the FNCC and CFU-C were also reduced in BU-treated mice, in conjunction with increases in serum FL levels. On days 72, 119 and 177 postdosing, several peripheral blood and bone marrow parameters remained reduced and the concentration of serum FL continued to be significantly increased. Linear regression analysis demonstrated significant correlations between the concentration of serum FL in BU-treated mice and peripheral blood and bone marrow parameters; this suggests the possible use of serum FL as a potential biomarker for drug-induced bone marrow injury.
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PMID:Serum FLT-3 ligand in a busulphan-induced model of chronic bone marrow hypoplasia in the female CD-1 mouse. 1833 32

Continuous identification and validation of novel drug targets require the development of rapid, reliable, and sensitive cell-based high-throughput screening (HTS) methods for proposed targets. Recently, the 5-HT(6) receptor (5-HT(6)R), a member of the class of recently discovered 5-HT receptors, has received considerable attention for its possible implications in depression, cognition, and anxiety. However, the cellular signaling mechanisms of 5-HT(6)R are poorly understood due to the lack of selective 5-HT(6)R ligands. In the present study, we examined functional coupling of the human 5-HT(6)R, 5-HT(7A)R, or 5-HT(7B)R with various Galpha-proteins (Galpha(15), Galpha(qs5), or Galpha(qG66Ds5)) to develop a reliable cell-based HTS method for 5-HT receptors. Among variable couplings between 5-HT receptors and G-proteins, we found that functional coupling of human 5-HT(6)R with Galpha(qG66Ds5) produced the highest levels of Ca(2+) signaling in HEK293 cells as measured by the fluorescence-based HTS plate reader, FDSS6000. After validation of this new 5-HT(6)R HTS system (Z'-factor = 0.56) in 96-well plates and characterization of the pharmacological profile of the 5-HT(6)R, we screened approximately 500 synthetic chemical compounds including butanamide and benzenesulfonamide derivatives. Based on this preliminary screening, we found that the butanamide derivative LSG11104 produced an IC(50) value of 6.3 microM. This compound will serve as a lead structure for further chemical modification to develop novel 5-HT(6)R ligands. Furthermore, we demonstrated that this HTS method can be utilized to identify proteins that modulate 5-HT(6)R function and present Fyn tyrosine kinase as an example, which is already known as a 5-HT(6)R interacting protein. Taken together, these results suggest that the 5-HT(6)R/Galpha(qG66Ds5) FDSS6000 system can be utilized to screen for selective 5-HT(6)R ligands and to examine any functional relationships between 5-HT(6)R and its binding proteins.
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PMID:Functional human 5-HT6 receptor assay for high throughput screening of chemical ligands and binding proteins. 1847 41

In order to elucidate the function of the targeting protein for Xenopus kinesin-like protein 2 (Xklp2) (TPX2) in the malignant transformation of human bronchial epithelial cells induced by anti-benzo[a]pyrene-trans-7, 8-dihydrodiol-9, 10-epoxide (anti-BPDE), TPX2 was characterized in cells at both the gene and the protein levels. TPX2 was present at higher levels in 16HBE-C cells than in 16HBE cells as demonstrated by two-dimensional gel electrophoresis, immunocytochemistry, Western blot analysis and RT-PCR. TPX2 was also detected in lung squamous-cell carcinoma tissues by immunohistochemistry, but not in normal lung tissues. Depression of TPX2 by RNA interference in 16HBE-C cells led to a decrease in cell proliferation, S-phase cell cycle arrest and cell apoptosis. Abnormal TPX2 tyrosine phosphorylation was detected in 16HBE-C cells, and this could be inhibited, to different degrees, by tyrosine kinase inhibitors. Inhibiting tyrosine phosphorylation in 16HBE-C cells by three selected tyrosine protein kinase inhibitors, tyrphostin 47, AG112 and AG555, caused G(0)/G(1)-phase cell cycle arrest. Our results suggest that anti-BPDE can cause the over-expression of TPX2 and its aberrant tyrosine phosphorylation. Misregulation of TPX2 affects the cell cycle state, proliferation rates and apoptosis.
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PMID:TPX2 in malignantly transformed human bronchial epithelial cells by anti-benzo[a]pyrene-7,8-diol-9,10-epoxide. 1872 71


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