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)

P2X(7) receptor subunits form homomeric ATP-gated, calcium-permeable cation channels. In this study, we used Western blots and immunocytochemistry to demonstrate that P2X(7) receptors are abundant on presynaptic terminals of mossy fiber synapses in the rat hippocampus. P2X(7)-immunoreactive protein was detected using a specific P2X(7) antibody in Western blots of protein isolated from whole hippocampus and from a subcellular fraction containing mossy fiber synaptosomes. P2X(7) immunoreactivity was colocalized with syntaxin 1A/B-immunoreactivity in mossy fiber terminals in the dentate hilus and stratum lucidum of CA3. Extracellular and whole-cell voltage-clamp recordings in CA3 revealed that bath application of the potent P2X(7) agonist 2',3'-O-(4-benzoylbenzoyl)-ATP (Bz-ATP) caused a long-lasting inhibition of neurotransmission at mossy fiber-CA3 synapses. Consistent with a presynaptic action at mossy fiber synapses, Bz-ATP had no significant effect on neurotransmission at associational-commissural synapses in CA3 but increased paired-pulse facilitation during depression of mossy fiber evoked currents. In addition, Bz-ATP had no postsynaptic effect on holding current or conductance of CA3 neurons. Bz-ATP-induced mossy fiber synaptic depression was blocked by the P2X(7) antagonist oxidized ATP but not by the P2X(1-3,5,6) antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid or the P2Y antagonist reactive blue 2. Finally, an antagonist of p38 MAP kinase activation [4-(4-fluorophenyl)2-(4-methylsulfinylphenyl)5-(4-pyridyl)imidazole] but not extracellular signal-regulated kinase 1/2 MAP kinase (2'-amino-3'-methoxyflavone) blocked the synaptic depression mediated by Bz-ATP, suggesting that this presynaptic inhibition was mediated by activation of p38 MAP kinase. The results of the present study demonstrate that activation of presynaptic P2X(7) receptors depresses mossy fiber-CA3 synaptic transmission through activation of p38 MAP kinase.
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PMID:Activation of presynaptic P2X7-like receptors depresses mossy fiber-CA3 synaptic transmission through p38 mitogen-activated protein kinase. 1212 56

The present study was designed to assess the effects of adenosine triphosphate (ATP) on hippocampal neurotransmissions under the normal and hypoxic/hypoglycemic conditions. ATP reversely depressed population spikes (PSs), which were monitored in the dentate gyrus of guinea pig hippocampal slices, in a dose-dependent manner at concentrations ranged from 0.1 micro M to 1 mM. A similar depression was obtained with the P(2) receptor agonist, alpha,beta-methylene ATP (alpha,beta-MeATP), and the effect was inhibited by the P(2) receptor antagonists, suramin and PPADS. The inhibitory action of ATP or alpha,beta-MeATP was inhibited by the gamma-aminobutyric acid(A) (GABA(A)) receptor antagonist, bicuculline, but it was not affected by theophylline, a broad inhibitor of adenosine (P(1)) receptors, tetraethylammonium, a broad inhibitor of K(+) channels, or ecto-protein kinase inhibitors. ATP or alpha,beta-MeATP enhanced GABA release from guinea pig hippocampal slices, that was inhibited by deleting extracellular Ca(2+) or in the presence of tetrodotoxin, while ATP had no effect on GABA release from cultured rat hippocampal astrocytes or postsynaptic GABA-gated channel currents in cultured rat hippocampal neurons. Twenty-minutes deprivation of glucose and oxygen from extracellular solution abolished PSs, the amplitude recovering to about 30% of basal levels 50 min after returning to normal conditions. ATP or alpha,beta-MeATP accelerated the recovery after hypoxic/hypoglycemic insult (approximately 80% of basal levels). Adenosine diphosphate and adenosine monophosphate accelerated the recovery, but to a much lesser extent, and adenosine had no effect. The results of the present study thus suggest that ATP inhibits neuronal activity by enhancing neuronal GABA release via a P(2) receptor, perhaps a P2X receptor, thereby protecting against hypoxic/hypoglycemic perturbation of hippocampal neurotransmission.
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PMID:Adenosine triphosphate accelerates recovery from hypoxic/hypoglycemic perturbation of guinea pig hippocampal neurotransmission via a P(2) receptor. 1236 1

Because gamma-aminobutyric acid(B) (GABA(B)) agonists produce strong antinociception, the present study analyzed if GABA(B) receptors might operate through depression of P2X(3) receptors responsible for fast adenosine triphosphate (ATP) currents involved in transmitting pain. On rat dorsal root ganglion (DRG) nociceptive neurons, inward currents induced by ATP were inhibited after 2 s or 60 s GABA application and unaffected after 10 s application. SKF-97541 or baclofen, potent GABA(B) agonists, mimicked only the late inhibition of ATP currents. The effect of SKF-97541 or GABA was observed even after their transient application prior to ATP. The GABA(B) antagonist CGP-52432 blocked the action of SKF-97541, suggesting a GABA(B) receptor-mediated mechanism (the GABA(A) antagonist picrotoxin was ineffective). It is suggested that, on nociceptive DRG neurons, GABA produced slow inhibition of P2X(3) receptors via metabotropic GABA(B) receptors.
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PMID:The ATP-mediated fast current of rat dorsal root ganglion neurons is a novel effector for GABA(B) receptor activation. 1258 26

The role of endogenous GABA and ATP in regulating transmitter release from primary afferent terminals in the superficial dorsal horn of the spinal cord is still controversial. ATP is co-released with GABA from some inhibitory dorsal horn neurons raising the possibility that ATP could act in concert with GABA to regulate transmitter release from primary afferent terminals if receptors to both transmitters are expressed there. Using electrophysiology together with immunocytochemistry, we have investigated the expression of ATP-gated P2X and GABAA receptors by identified subpopulations of dorsal root ganglion (DRG) neurons known to project primarily to the superficial dorsal horn. Expression of the heat-sensitive vanilloid receptor 1 (VR1) and sensitivity to capsaicin were used to characterize DRG neurons sensitive to noxious heat. Both P2X and GABAA receptors were expressed on the majority of DRG neurons examined. Recording compound action potentials (CAPs) from dorsal roots in the presence of muscimol, alpha,beta-methylene-ATP (alpha,beta-meATP) or capsaicin resulted in depression of CAP in the slow and medium conducting fibres, indicating cognate receptor expression on the small diameter axons. Dorsal root-evoked dorsal root potentials (DR-DRPs), reflecting depolarization of primary afferent terminals by endogenously released substances, were depressed by the GABAA receptor antagonist SR95531 and alpha,beta-meATP. These results suggest that GABAA and P2X receptors are expressed on DRG cell bodies and slow fibre axons, many of which are heat-nociceptive. These fibres project to the superficial lamina of the dorsal horn where the receptors may function to modulate transmitter release near their central terminals.
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PMID:Localization and function of ATP and GABAA receptors expressed by nociceptors and other postnatal sensory neurons in rat. 1266 15

In 1995 the P2X3 receptor was found to be expressed at high levels in nociceptive sensory neurones, consistent with earlier reports that ATP induced pain in humans and animals. At first it was thought that ATP was most likely to play a role in acute pain, following its release from damaged or stressed cells and since then a wide variety of experimental techniques and approaches have been used to study this possibility. Whilst it is clear that exogenous and endogenous ATP can indeed acutely stimulate sensory neurones, more recent reports using gene knockout and antisense oligonucleotide technologies, and a novel, selective P2X3 antagonist, A-317491, all indicate that ATP and P2X3 receptors are more likely to be involved in chronic pain conditions, particularly chronic inflammatory and neuropathic pain. These reports indicate that P2X3 receptors on sensory nerves may be tonically activated by ATP released from nearby damaged or stressed cells, or perhaps from the sensory nerves themselves. This signal, when transmitted to the CNS, will be perceived consciously as chronic pain. In addition, it is now clear that several subtypes of P2Y receptor are also expressed in sensory neurones. Although their distribution and functions have not been as widely studied as P2X receptors, the effects that they mediate indicate that they might also be considered as therapeutic targets in the treatment of pain. Although our ability to treat persistent painful conditions, such as chronic inflammatory and neuropathic pain, has improved in recent years, these conditions are often resistant to currently available therapies, such as opioids or non-steroidal anti-inflammatory drugs. This reflects a limited understanding of the underlying pathophysiology. It is now clear that the development and maintenance of chronic pain are mediated by multiple factors, but many of these factors, and the receptors and mechanisms through which they act, remain to be identified. Chronic pain is debilitating and can greatly decrease quality of life, not just due to the pain per se, but also because of the depression that can often ensue. Thus a greater understanding of the mechanisms that underlie chronic pain will help identify new targets for novel analgesics, which will be of great therapeutic benefit to many people.
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PMID:Crossing the pain barrier: P2 receptors as targets for novel analgesics. 1451 72

ATP is an important extracellular messenger in the CNS. In the hippocampus, a brain structure relevant for learning and memory processes, it acts both as a modulator and as a mediator of synaptic transmission, with implications for synaptic plasticity phenomena. Recent evidence suggests that ATP modulates activity-dependent long-term potentiation (LTP) of Schaffer collateral-CA1 synapses. However, it remains unclear if ATP also modulates LTP counterpart's phenomenon, long-term depression (LTD), in the rat hippocampus. This study investigated the effect of ATP analogues on homosynaptic LTD, induced by low-frequency stimulation of the Schaffer collaterals (1 Hz; 900 pulses) in the CA1 region of young rat hippocampal slices. The metabolically stable ATP analogues beta,gamma-ImATP (20 microM), a P2 receptor agonist, and alpha,beta-MeATP (20 microM), a preferential P2X(1,3) receptor agonist, did not modify LTD (LTD values of 14.7+/-0.5% and 14.1+/-3% for aCSF controls and of 15.1+/-4% and 19.0+/-5.2% for beta,gamma-ImATP and alpha,beta-MeATP, respectively). The ATP analogue beta,gamma-ImATP (20 microM) did not modify LTD also in the presence of the adenosine A1 receptor antagonist DPCPX (50 nM) (21.5+/-4.2% for DPCPX only and of 23.8+/-8.9% for DPCPX plus beta,gamma-ImATP). Finally, the preferential P2X(1,3) receptor antagonist NF023 (10 microM) had also no effect on LTD (18.6+/-5.2% for aCSF and of 18.7+/-5.2% for NF023). The present results suggest that ATP does not modulate activity-dependent homosynaptic LTD in the rat CA1 hippocampal region by activating P2 receptors.
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PMID:Long-term depression is not modulated by ATP receptors in the rat CA1 hippocampal region. 1588 30

Activation of presynaptic receptors plays an important role in modulation of transmission at many synapses, particularly during high-frequency trains of stimulation. Adenosine-triphosphate (ATP) is coreleased with several neurotransmitters and acts at presynaptic sites to reduce transmitter release; such presynaptic P2X receptors occur at inhibitory and excitatory terminals in the medial nucleus of the trapezoid body (MNTB). We have investigated the mechanism of purinergic modulation during high-frequency repetitive stimulation at the calyx of Held synapse. Suppression of calyceal excitatory postsynaptic currents (EPSCs) by ATP and ATPgammaS (100 microM) was mimicked by adenosine application and was blocked by DPCPX (10 microM), indicating mediation by adenosine A1 receptors. DPCPX enhanced EPSC amplitudes during high-frequency synaptic stimulation, suggesting that adenosine has a physiological role in modulating transmission at the calyx. The Luciferin-Luciferase method was used to probe for endogenous ATP release (at 37 degrees C), but no release was detected. Blockers of ectonucleotidases also had no effect on endogenous synaptic depression, suggesting that it is adenosine acting on A1 receptors, rather than degradation of released ATP, which accounts for presynaptic purinergic suppression of synaptic transmission during physiological stimulus trains at this glutamatergic synapse.
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PMID:Endogenous activation of adenosine A1 receptors, but not P2X receptors, during high-frequency synaptic transmission at the calyx of Held. 1648 62

Extracellular adenosine 5'-triphosphate (ATP) was proposed to be an activity-dependent signaling molecule that regulates glia-glia and glia-neuron communications. ATP is a neurotransmitter of its own right and, in addition, a cotransmitter of other classical transmitters such as glutamate or GABA. The effects of ATP are mediated by two receptor families belonging either to the P2X (ligand-gated cationic channels) or P2Y (G protein-coupled receptors) types. P2X receptors are responsible for rapid synaptic responses, whereas P2Y receptors mediate slow synaptic responses and other types of purinergic signaling involved in neuronal damage/regeneration. ATP may act at pre- and postsynaptic sites and therefore, it may participate in the phenomena of long-term potentiation and long-term depression of excitatory synaptic transmission. The release of ATP into the extracellular space, e.g., by exocytosis, membrane transporters, and connexin hemichannels, is a widespread physiological process. However, ATP may also leave cells through their plasma membrane damaged by inflammation, ischemia, and mechanical injury. Functional responses to the activation of multiple P2 receptors were found in neurons and glial cells under normal and pathophysiological conditions. P2 receptor-activation could either be a cause or a consequence of neuronal cell death/glial activation and may be related to detrimental and/or beneficial effects. The present review aims at demonstrating that purinergic mechanisms correlate with the etiopathology of brain insults, especially because of the massive extracellular release of ATP, adenosine, and other neurotransmitters after brain injury. We will focus in this review on the most important P2 receptor-mediated neurodegenerative and neuroprotective processes and their beneficial modulation by possible therapeutic manipulations.
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PMID:P2 receptors and neuronal injury. 1664 49

Purines have key roles in neurotransmission and neuromodulation, with their effects being mediated by the purine and pyrimidine receptor subfamilies, P1, P2X and P2Y. Recently, purinergic mechanisms and specific receptor subtypes have been shown to be involved in various pathological conditions including brain trauma and ischaemia, neurodegenerative diseases involving neuroimmune and neuroinflammatory reactions, as well as in neuropsychiatric diseases, including depression and schizophrenia. This article reviews the role of purinergic signalling in CNS disorders, highlighting specific purinergic receptor subtypes, most notably A(2A), P2X(4) and P2X(7), that might be therapeutically targeted for the treatment of these conditions.
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PMID:Purinergic signalling and disorders of the central nervous system. 1859 79

Previous work has shown that ATP-gated P2X2 receptors are expressed in excitatory nerve terminals onto stratum radiatum interneurons in the mouse hippocampal CA1 region. At these synapses receptor activation results in calcium-dependent facilitation of miniature and spontaneous EPSC frequency. In this study I determined if activation of presynaptic P2X receptors produces these effects by utilizing the vesicles underlying action potential dependent release. Brief trains of electrical stimuli caused short-term synaptic depression of excitatory synapses onto interneurons, in a manner consistent with depletion of the readily releasable pool of vesicles. P2X receptor activation increased the frequency of spontaneous EPSCs, but unexpectedly evoked little effect on synaptic depression. This suggests that P2X receptor activation does not markedly draw on the vesicles underlying action potential dependent glutamate release. However asynchronous EPSCs were increased following synaptic depression and a component of these appeared to be initiated by endogenously released ATP acting on presynaptic P2X receptors. Unexpectedly, the data suggest P2X receptor activation initiates a form of asynchronous glutamate release, rather than detectably affecting the vesicles underlying action potential evoked release.
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PMID:ATP-gated P2X receptors on excitatory nerve terminals onto interneurons initiate a form of asynchronous glutamate release. 1860 37


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