UMLS:C0011570 - FACTA Search

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)

Leukocyte infiltration in the CNS after trauma or inflammation is triggered in part by upregulation of the chemokine, monocyte chemoattractant protein-1 (MCP-1), in astrocytes. However the signals that induce the upregulation of MCP-1 in astrocytes are unknown. We have investigated the roles for ATP P2X7 receptor activation because ATP is an intercellular signaling transmitter that is released in both trauma and inflammation and P2X7 receptors are involved in immune system signaling. Astrocytes in primary cell culture and acutely isolated from the hippocampus were immunopositive for P2X7 receptors. In astrocyte cultures, application of the selective P2X7 agonist, benzoyl-benzoyl ATP (Bz-ATP), activated MAP kinases extracellular signal receptor-activated kinase 1 (ERK1), ERK2, and p38. Purinergic antagonists depressed this activation with a profile suggesting P2X7 receptors. Bz-ATP also increased MCP-1 expression in cultured astrocytes, and again P2X7 antagonists prevented this increase. Blocking either the ERK1/ERK2 or the p38 pathway (with PD98059 or SB203580, respectively) significantly inhibited Bz-ATP-induced MCP-1 expression. Coapplication of both antagonists caused a greater depression. We also tested the roles for ATP receptor activation in inducing MCP-1 upregulation in corticectomy, an in vivo model of trauma. This model of cortical trauma was previously shown to increase MCP-1 expression in vivo principally in astrocytes. Suramin, a wide-spectrum purinergic receptor antagonist, significantly depressed the rapid (3 hr) trauma-induced increase in MCP-1 mRNA. These data indicate that purinergic transmitter receptors in astrocytes are important in regulating chemokine synthesis. The regulation of MCP-1 in astrocytes by ATP may be important in mediating communication with hematopoietic inflammatory cells.
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PMID:P2X7-like receptor activation in astrocytes increases chemokine monocyte chemoattractant protein-1 expression via mitogen-activated protein kinase. 1154 24

The ionotropic and cytolytic P2X7 receptor is typically found on immune cells, where it is involved in the release of cytokines. Recently, P2X7 receptors were reported to be localized to presynaptic nerve terminals and to modulate transmitter release. In the present study, we reassessed this unexpected role of P2X7 receptors at hippocampal mossy fiber-CA3 synapses. In agreement with previous findings, the widely used P2X7 agonist 2'-3'-O-(4-benzoylbenzoyl)-adenosine-5'-triphosphate (BzATP) clearly depressed field potentials (fEPSPs); however, no evidence for an involvement of P2X7 receptors could be obtained. First, depression of fEPSPs by BzATP was unchanged in P2X7-/- mice. Second, experiments using P2X7-/- mice, immunohistochemistry, and electron microscopy showed that the antigen detected by frequently used P2X7 antibodies is not compatible with a plasmalemmal P2X7 receptor. Third, BzATP did not alter Ca2+ levels in synaptic terminals. In contrast, the depression of fEPSPs by BzATP was fully blocked by adenosine (A1) receptor antagonists. Furthermore, the application of BzATP also activated postsynaptic A1 receptor-coupled K+ channels. This effect of BzATP was mimicked by ATP and adenosine and was completely prevented by enzymes specifically degrading adenosine. Activation of A1-coupled K+ channels by BzATP was dependent on ecto-nucleotidases, extracellular enzymes that convert ATP to adenosine. Moreover, the opening of A1-coupled K+ channels by BzATP was dependent on nucleoside transporters. Taken together, our results indicate that BzATP is extracellularly catabolized to Bz-adenosine and subsequently hetero-exchanged for intracellular adenosine and then depresses mossy fiber fEPSPs through presynaptic A1 receptors rather than through P2X7 receptors. Thus, the present study casts doubts on the neuronal localization of P2X7 receptors in rodent hippocampus.
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PMID:Ecto-nucleotidases and nucleoside transporters mediate activation of adenosine receptors on hippocampal mossy fibers by P2X7 receptor agonist 2'-3'-O-(4-benzoylbenzoyl)-ATP. 1530 46

The metabolic and developmental depression commonly observed during natural states of dormancy, such as diapause and quiescence, is typically accompanied by an increase in the intracellular ratio of AMP to ATP. We investigated the impact of artificially increasing the AMP-to-ATP ratio in mouse macrophages. Evidence is presented here that the P2X7 receptor channel can be used as an effective means to load cells with membrane-impermeable compounds. Intracellular loading of adenosine-5'-O-thiomonophosphate (AMPS), a nonhydrolyzable analog of 5'-AMP and potent activator of AMP-activated protein kinase, significantly depresses metabolism and proliferation of macrophages. The intracellular effective AMP-to-ATP ratio obtained (the sum of AMPS plus endogenous 5'-AMP) was 0.073, well above that reported to activate AMP-activated protein kinase in vitro. Optimizing both the conditions under which the P2X7 receptor channel is opened and the duration of opening facilitates high analog uptake and approximately 98% survivorship. An advantage to AMPS is its minimal impact on other components of the nucleotide pool, most notably the unchanged concentration of ADP. An alternative way to shift the effective AMP-to-ATP ratio is by incubation with the membrane-permeable compound 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR), which is phosphorylated intracellularly to form the 5'-AMP analog ZMP. Despite a rapid intracellular accumulation of AICAR, conversion to ZMP was slow and inefficient. Furthermore, AICAR incubation increased cellular ADP, and, although cell proliferation was depressed, the overall cellular energy flow was unchanged. The rapid action of AMPS avoids upregulation of compensatory metabolic pathways and may provide a viable approach for promoting cell stasis.
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PMID:Depression of cell metabolism and proliferation by membrane-permeable and -impermeable modulators: role for AMP-to-ATP ratio. 1545 72

The P2RX7 gene (coding for P2X7 purinergic receptor) has been suggested as a novel candidate gene for major depressive disorder (MDD) and bipolar disorder (BPD). The proposed risk allele (G-allele) of the rs2230912 polymorphism results in an amino acid change at the 460th position, marking this genetic variation a possibly functional one. Here we present a case-control analysis of 171 patients diagnosed with MDD or BPD and 178 controls, as well as a dimensional approach using the Hospital Anxiety and Depression Scale (HADS) for studying the Gln460Arg polymorphism of the P2RX7 gene as a genetic risk factor in depression. While case-control analysis did not show significant difference between the groups, a significant association was found between the P2RX7 polymorphism and the HADS scales in the clinical group (MANOVA P = 0.001). Both anxiety and depression scores increased as the number of G-allele increased in the genotype groups (ANOVA for HADS-anxiety: P = 0.01, HADS-depression: P < 0.001). A significant interaction of clinical status and the P2RX7 polymorphism was also found for the depression scale (MANOVA P = 0.025, subsequent ANOVA for anxiety: P = 0.252; depression: P = 0.002). Whereas patients with G-allele-present genotypes showed more elevated depression scores, level of depression in the control group was not affected by the P2RX7 genotype. In conclusion, case-control analysis did not reveal significant results, but using a symptom severity scale we could support the association between depressive disorder and the G-allele of the Gln460Arg polymorphism in the P2RX7 gene.
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PMID:Association between depression and the Gln460Arg polymorphism of P2RX7 gene: a dimensional approach. 1945 4

Major depressive disorder is highly prevalent and remains inadequately treated. Numerous studies have demonstrated that modulation of ion channel activity can reduce depression-like behavior in animal models or depressive symptoms in humans. N-Methyl-D-aspartate and nicotinic acetylcholine receptor blockers have demonstrated promise as potential antidepressant agents in humans. Moreover, behavioral and physiological findings have provided evidence that the more recently characterized ion channel TWIK-related K+ channel-1 is a potential antidepressant target; however, drugs directed at this channel have yet to undergo clinical testing. Animal studies and genetic association findings also suggest that a number of other channel types, including voltage-gated calcium (N-type), potassium (Kv7), serotonin 5-HT3 and purinergic P2X7 channels, may influence depression-like behavior. The therapeutic utility of some ion channels will be limited by their role in multiple physiological or pathophysiological processes. Nevertheless, a number of strategies are being employed to provide improved specificity of action.
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PMID:Ion channels as potential targets for the treatment of depression. 1872 15

P2X7 purinergic receptors have been implicated in chronic neuropathic and neuroinflammatory pain as well as in depression. These receptors are predominantly found in the central nervous system on microglial cells and on glutamatergic nerve terminals. Here, we develop hypotheses concerning mechanisms by which transient high-frequency impulse firing in glutamatergic terminals, such as occurs in nociceptor terminals accompanying neuropathic/neuroinflammatory pain, can lead to long-lasting changes in neural network function that is mediated by surrounding glial cells. The hypothesis consists of two parts. In the first, glutamate released by low-frequency (2Hz) terminal action potentials is insufficient to generate postsynaptic action potentials, but these are generated by brief high-frequency input bursts. Glutamate released by these bursts is partly removed by transporters on the enveloping astrocyte processes and also excites AMPA receptors on these processes, which then release ATP. This ATP is partly metabolised to adenosine, which acts on presynaptic A1 receptors to inhibit glutamate release. The remaining ATP acts on the presynaptic P2X7 receptors to facilitate glutamate release by both the high-frequency burst of action potentials as well as by a continuous low-frequency (2Hz) action potential firing that occurs in the absence of a neuropathic/neuroinflammatory insult. The positive feedback of terminal glutamate release, triggering astrocyte ATP release and leading to further glutamate release through activation of P2X7 receptors, is then sufficient to allow the normal low-frequency (2Hz) action potentials to now elicit postsynaptic action potentials after the insult is removed. In the second part of this model, the high concentration of ATP derived from astrocytes at the terminal attracts microglia by chemotaxis. The P2X7 receptors on these microglia are then engaged, resulting in microglia secreting the cytokine TNFalpha. This acts on postsynaptic TNF-R1 receptors to increase the number of AMPA receptors there, thus enhancing the efficacy of synaptic transmission. The TNFalpha also acts on presynaptic TNF-R1 to increase the amount of glutamate released by each nerve terminal impulse. Experimental tests can be made of this hypothesis that P2X7 receptors on the presynaptic terminal and those on the microglia synergistically act to ensure feedback pathways that reset to a high level the efficacy of synaptic transmission, thus ensuring chronic neuropathic/neuroinflammatory pain even when the initial insult has subsided.
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PMID:P2X7 regenerative-loop potentiation of glutamate synaptic transmission by microglia and astrocytes. 1964 12

Accumulating evidence indicate that the gap-junction inhibitor carbenoxolone (CBX) regulates neuronal synchronization, depresses epileptiform activity and has a neuroprotective action. These CBX effects do not depend solely on its ability to inhibit gap junction channels formed by connexins (Cx), but the underlying mechanisms remain to be elucidated. Here we addressed the questions whether CBX modulates volume-regulated anion channels (VRAC) involved in the regulatory volume decrease and regulates the associated release of excitatory amino acids in cultured rat cortical astrocytes. We found that CBX inhibits VRAC conductance with potency comparable to that able to depress the activity of the most abundant astroglial gap junction protein connexin43 (Cx43). However, the knock down of Cx43 with small interfering RNA (siRNA) oligonucleotides and the use of various pharmacological tools revealed that VRAC inhibition was not mediated by interaction of CBX with astroglial Cx proteins. Comparative experiments in HEK293 cells stably expressing another putative target of CBX, the purinergic ionotropic receptor P2X7, indicate that the presence of this receptor was not necessary for CBX-mediated depression of VRAC. Finally, we show that in COS-7 cells, which are not endowed with pannexin-1 protein, another astroglial plasma membrane interactor of CBX, VRAC current retained its sensitivity to CBX. Complementary analyses indicate that the VRAC-mediated release of excitatory amino acid aspartate was decreased by CBX. Collectively, these findings support the notion that CBX could affect astroglial ability to modulate neuronal activity by suppressing excitatory amino acid release through VRAC, thereby providing a possible mechanistic clue for the neuroprotective effect of CBX in vivo.
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PMID:Carbenoxolone inhibits volume-regulated anion conductance in cultured rat cortical astroglia. 1971 39

The recent discovery of post-transcriptional regulation by microRNAs (miRNAs) drew our attention to SNPs of putative miRNA target sites in candidate genes of depression-related psychiatric disorders. The P2RX7 (purinergic receptor P2X, ligand-gated ion channel, 7) gene has been suggested as a candidate for major depressive and bipolar disorder, because of repeated associations with the rs2230912 (Gln460Arg) polymorphism. As this polymorphism is located at the end of the coding region, we considered a possible linkage with SNP(s) in putative miRNA target sites of the 3' untranslated region. Based on our in silico search, the rs1653625 fulfilled this criterion. This SNP, however, is surrounded with polycytosine and polyadenine tracts, which hindered its analysis until now. In this study, we describe a readily applicable genotyping method for rs1653625 by applying a primer that introduces mismatched nucleotides to create a restriction enzyme cleavage site. The resulting allele-specific products with 19 base pair difference were separated by both traditional horizontal agarose gel electrophoresis and multicapillary gel electrophoresis. The developed genotyping method was applied in our depression-related association study.
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PMID:Analysis of a polymorphic microRNA target site in the purinergic receptor P2RX7 gene. 2044 88

There is considerable evidence suggesting genetic factors play an important role in the pathophysiology of depression, possibly by increasing susceptibility to repeated environmental stressors. Recent linkage studies have associated a polymorphism of the gene coding for the P2X7 receptor (P2X7R) with both major depressive disorder and bipolar disorder. Here we assessed whether P2X7 deletion affected the behavioural and neural response to repeated stress. P2X7R knockout (P2X7-/-) mice were subjected to the forced swim test for three consecutive days and neuronal activation in response to the third exposure was assessed using c-Fos immunohistochemistry. In addition, anxiety was evaluated in another group of P2X7-/- mice using the elevated plus maze (EPM) and light dark emergence (LDE) tests. Equivalent levels of immobility were observed in P2X7-/- mice and wild-type (WT) mice on the first exposure to forced swim, but much greater immobility was seen in WT mice on second and third exposures. This suggests that P2X7-/- mice exhibit an impaired adaptive coping response to repeated stress. Reinforcing this view, c-Fos expression in the dentate gyrus of the hippocampus and in the basolateral amygdala was seen in WT mice but not P2X7-/- mice following repeated forced swim. In addition, decreased locomotor activity was detected in P2X7-/- mice without any specific effects on anxiety in the LDE test. However, P2X7-/- mice showed greater anxiety-like behaviour in the EPM. These data suggest that the P2X7R may be involved in the adaptive mechanisms elicited by exposure to repeated environmental stressors that leads to the development of depression-like behaviours. This suggests that P2X7R antagonists may be useful therapeutics for the treatment of major depression, possibly by increasing resilience in the face of repeated stress.
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PMID:Resilience and reduced c-Fos expression in P2X7 receptor knockout mice exposed to repeated forced swim test. 2166 37

It is proposed that ATP is released from both neurons and glia during electroconvulsive therapy (ECT) and that this leads to reduction of depressive behaviour via complex stimulation of neurons and glia directly via P2X and P2Y receptors and also via P1 receptors after extracellular breakdown of ATP to adenosine. In particular, A(1) adenosine receptors inhibit release of excitatory transmitters, and A(2A) and P2Y receptors may modulate the release of dopamine. Sequential ECT may lead to changes in purinoceptor expression in mesolimbic and mesocortical regions of the brain implicated in depression and other mood disorders. In particular, increased expression of P2X7 receptors on glial cells would lead to increased release of cytokines, chemokines and neurotrophins. In summary, we suggest that ATP release following ECT involves neurons, glial cells and neuron-glial interactions acting via both P2 and after breakdown to adenosine via P1 receptors. We suggest that ecto-nucleotidase inhibitors (increasing available amounts of ATP) and purinoceptor agonists may enhance the anti-depressive effect of ECT.
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PMID:Electroconvulsive therapy: a novel hypothesis for the involvement of purinergic signalling. 2169 18

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