Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Long-term depression (LTD) is a use-dependent decrease in synaptic efficacy widely recognized as a form of synaptic plasticity related to cognitive function in the central nervous system. Such response has previously not been demonstrated in autonomic ganglia. In the isolated superior cervical ganglion (SCG) of the rat (superfused with Locke solution containing 100 microM choline), low-frequency stimulation (LFS, 3-5 Hz/15 min) of the preganglionic nerve produced a long-lasting (up to 3 h ), significant (20-40%) decrease in the amplitude of the extracellularly recorded postganglionic compound action potential. Pretreatment of ganglia with the 5-HT(3) receptor antagonist tropisetron (0.5 microM) completely prevented the induction of ganglionic LTD (gLTD). Treatment of ganglia with the 5-HT(3) receptor antagonist MDL 72222 (0.5 microM) during the maintenance phase of established gLTD (1 h after LFS) antagonized the LFS-induced depression. Inhibition of nitric oxide (NO) synthase with l-NOARG (20-50 microM), applied before or after LFS, failed to affect the expression of gLTD. Additionally, pretreatment with the protein synthesis inhibitor emetine (1 microM) totally prevented the expression of gLTD. However, inhibition of protein phosphatase with cantharidin (30 microM) did not interfere with the expression of gLTD. These results indicate the presence of LTD in the rat SCG and suggest that expression of gLTD involves activation of 5-HT(3) receptor.
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PMID:Long-term depression in the superior cervical ganglion of the rat. 1871 51

Abnormal protein phosphorylation has been associated with several neurodegenerative disorders, including Alzheimer's disease (AD). Abeta is the toxic peptide that results from proteolytic cleavage of the Alzheimer's amyloid precursor protein, a process where protein phosphatases are known to impact. The data presented here demonstrates that protein phosphatase 1 (PP1), an abundant neuronal serine/threonine-specific phosphatase highly enriched in dendritic spines, is specifically inhibited by Abeta peptides both in vitro and ex vivo. Indeed, the pathologically relevant Abeta(1-40) and Abeta(1-42) peptides, as well as Abeta(25-35), specifically inhibit PP1 with low micromolar potency, as compared to inactive controls and other disease related peptides (e.g. the prion related Pr(118-135) and Pr(106-126)). Interestingly, PP1 inhibition is increased by Abeta aggregation, indicating a possible direct neurotoxic effect of the aggregated peptide. PP1 involvement in processes like long-term depression, memory and learning, and synaptic plasticity, prompt us to suggest that PP1 may constitute an important physiological target for Abeta and, therefore, increased Abeta production and/or aggregation may lead to abnormal PP1 activity and likely contribute to the progressive neuropsychiatric AD condition. Thus, PP1 activity and levels constitute potential biomolecular candidates for diagnostics and therapeutics.
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PMID:PP1 inhibition by Abeta peptide as a potential pathological mechanism in Alzheimer's disease. 1902 67

Transmitter release at high probability phasic synapses of crayfish neuromuscular junctions depresses by over 50% in 60 min when stimulated at 0.2 Hz. Inhibition of the protein phosphatase calcineurin by intracellular pre-synaptic injection of autoinhibitory peptide inhibited low-frequency depression (LFD) and resulted in facilitation of transmitter release. Since this inhibitor had no major effects when injected into the post-synaptic cell, only pre-synaptic calcineurin activity is necessary for LFD. To examine changes in phosphoproteins during LFD we performed a phosphoproteomic screen on proteins extracted from motor axons and nerve terminals after LFD induction or treatment with various drugs that affect kinase and phosphatase activity. Proteins separated by PAGE were stained with phospho-specific/total protein ratio stains (Pro-Q Diamond/SYPRO Ruby) to identify protein bands for analysis by mass spectrometry. Phosphorylation of actin and tubulin decreased during LFD, but increased when calcineurin was blocked. Tubulin and phosphoactin immunoreactivity in pre-synaptic terminals were also reduced after LFD. The actin depolymerizing drugs cytochalasin and latrunculin and the microtubule stabilizer taxol inhibited LFD. Therefore, dephosphorylation of pre-synaptic actin and tubulin and consequent changes in the cytoskeleton may regulate LFD. LFD is unlike long-term depression found in mammalian synapses because the latter requires in most instances post-synaptic calcineurin activity.Thus, this simpler invertebrate synapse discloses a novel pre-synaptic depression mechanism.
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PMID:Calcineurin and cytoskeleton in low-frequency depression. 1920 Mar 40

In response to energy stress (and elevated AMP), the AMP-activated protein kinase (AMPK) coordinates the restoration of energy homeostasis. We determined that AMPK is activated in a model system (desert snail Otala lactea) during a physiological state of profound metabolic rate depression (estivation) in the absence of a rise in AMP. Kinetic characterization indicated a strong increase in AMPK activity and phosphorylation in estivation, consistent with an increase in P-Ser428 LKB, an established regulator of AMPK. Accordingly, approximately 2-fold increases in AMPKalpha1 protein and activity were observed with LKB1 immunoprecipitates from estivating snails. In vitro studies determined that AMPK in crude extracts was activated in the presence of cGMP and deactivated in conditions that permitted protein phosphatase type-2A (PP2A) activity. Furthermore, AMPKalpha1 protein and activity increased in PKG immunoprecipitates from estivating tissues, suggesting a novel role for PKG in the regulation of AMPK in vivo. We evaluated several downstream targets of AMPK. Acetyl-CoA carboxylase (ACC) activity was strongly inhibited in estivation, consistent with increased P-Ser79 content, and in vitro stimulation of AMPK negated citrate's ability to stimulate ACC aggregation. Analysis of other targets revealed a strong decrease in PPARgamma-coactivator 1alpha expression in both tissues, which was related to decreased gluconeogenic protein expression in hepatic tissue, but no changes in mitochondrial biogenesis markers in muscle. We concluded that AMPK activation in O. lactea aids in facilitating the suppression of anabolic pathways, without necessarily activating ATP-generating catabolism.
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PMID:The regulation of AMPK signaling in a natural state of profound metabolic rate depression. 1975 61

Alzheimer's disease (AD) is a progressive neurodegenerative disorder caused by an increase in amyloid metabolism. The calcium hypothesis of AD explores how activation of the amyloidogenic pathway may function to remodel the neuronal Ca(2+) signaling pathways responsible for cognition. Hydrolysis of the beta-amyloid precursor protein (APP) yields two products that can influence Ca(2+) signaling. Firstly, the amyloids released to the outside form oligomers that enhance the entry of Ca(2+) that is pumped into the endoplasmic reticulum (ER). An increase in the luminal level of Ca(2+) within the ER enhances the sensitivity of the ryanodine receptors (RYRs) to increase the amount of Ca(2+) being released from the internal stores. Secondly, the APP intracellular domain may alter the expression of key signaling components such as the RYR. It is proposed that this remodeling of Ca(2+) signaling will result in the learning and memory deficits that occur early during the onset of AD. In particular, the Ca(2+) signaling remodeling may erase newly acquired memories by enhancing the mechanism of long-term depression that depends on activation of the Ca(2+)-dependent protein phosphatase calcineurin. The alteration in Ca(2+) signaling will also contribute to the neurodegeneration that characterizes the later stages of dementia.
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PMID:Calcium hypothesis of Alzheimer's disease. 1979 32

Behavioural symptoms are a significant problem in Alzheimer's disease (AD). Symptoms including agitation/aggression and psychosis reduce patient quality of life, significantly increase caregiver burden, and often trigger nursing home placement. Underlying changes in the serotonergic, noradrenergic and cholinergic systems have been linked to some behavioural problems, however, the use of antipsychotics in this population has been associated with significant safety concerns. A role for the glutamate system in schizophrenia, as well as in anxiety and depression, has been suggested, and evidence is emerging for a role for dysfunctional glutamate neurotransmission (via N-methyl-D-aspartate (NMDA) receptors) in certain behavioural changes in dementia. For example, the NMDA receptor antagonist, memantine has been shown to improve cognition, function (activities of daily living, ADLs) and, more recently, agitation/aggression, and delusions in AD patients. To date, little information is available regarding the neurochemical basis of agitation/aggression. However, the frontal and cingulate cortices--specifically, the formation of neurofibrillary tangles in glutamatergic pyramidal neurones of these areas--are proposed as regional substrates of these behaviours. Given that memantine displays a favourable tolerability profile, it is relevant to investigate the underlying mechanism linking memantine with the behavioural elements of AD. One hypothesis proposes that memantine corrects dysfunctional glutamatergic neurotransmission in the frontal and cingulate cortices, thereby normalising pathways responsible for causing agitation. An alternative hypothesis is based on the observation that increased tangle formation is associated with agitation, and on recent studies where memantine has been shown to reduce tau phosphorylation via glycogen synthase kinase (GSK)-3 or activation of protein phosphatase (PP)-2A, which might subsequently lead to reduced agitation.
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PMID:Altered glutamate neurotransmission and behaviour in dementia: evidence from studies of memantine. 2002 48

The cellular properties of long-term potentiation (LTP) following pairing of pre- and postsynaptic activity were examined at a known glutamatergic synapse in the leech, specifically between the pressure (P) mechanosensory and anterior pagoda (AP) neurons. Stimulation of the presynaptic P cell (25 Hz) concurrent with a 2 nA depolarization of the postsynaptic AP cell significantly potentiated the P-to-AP excitatory postsynaptic potential (EPSP) in an N-methyl-d-aspartate receptor (NMDAR)-dependent manner based on inhibitory effects of the NMDAR antagonist MK801 and inhibition of the NMDAR glycine binding site by 7-chlorokynurenic acid. LTP was blocked by injection of bis-(o-aminophenoxy)-N,N,N',N'-tetraacetic acid (BAPTA) into the postsynaptic (AP) cell, indicating a requirement for postsynaptic elevation of intracellular Ca(2+). Autocamtide-2-related inhibitory peptide (AIP), a specific inhibitor of Ca(2+)/calmodulin-dependent kinase II (CaMKII), and Rp-cAMP, an inhibitor of protein kinase A (PKA), also blocked pairing-induced potentiation, indicating a requirement for activation of CaMKII and PKA. Interestingly, application of AIP during pairing resulted in significantly depressed synaptic transmission. Co-application of AIP with the protein phosphatase inhibitor okadaic acid restored synaptic transmission to baseline levels, suggesting an interaction between CaMKII and protein phosphatases during induction of activity-dependent synaptic plasticity. When postsynaptic activity preceded presynaptic activity, NMDAR-dependent long-term depression (LTD) was observed that was blocked by okadaic acid. Postsynaptic injection of botulinum toxin blocked P-to-AP potentiation while postsynaptic injection of pep2-SVKI, an inhibitor of AMPA receptor endocytosis, inhibited LTD, supporting the hypothesis that glutamate receptor trafficking contributes to both LTP and LTD at the P-to-AP synapse in the leech.
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PMID:Co-induction of LTP and LTD and its regulation by protein kinases and phosphatases. 2045 59

Long-term depression (LTD) is a form of synaptic plasticity that may contribute to information storage in the central nervous system. Here we report that LTD can be elicited in layer 5 pyramidal neurons of the rat prefrontal cortex by pairing low frequency stimulation with a modest postsynaptic depolarization. The induction of LTD required the activation of both metabotropic glutamate receptors of the mGlu1 subtype and voltage-sensitive Ca(2+) channels (VSCCs) of the T/R, P/Q and N types, leading to the stimulation of intracellular inositol trisphosphate (IP3) receptors by IP3 and Ca(2+). The subsequent release of Ca(2+) from intracellular stores activated the protein phosphatase cascade involving calcineurin and protein phosphatase 1. The activation of purinergic P2Y(1) receptors blocked LTD. This effect was prevented by P2Y(1) receptor antagonists and was absent in mice lacking P2Y(1) but not P2Y(2) receptors. We also found that activation of P2Y(1) receptors inhibits Ca(2+) transients via VSCCs in the apical dendrites and spines of pyramidal neurons. In addition, we show that the release of ATP under hypoxia is able to inhibit LTD by acting on postsynaptic P2Y(1) receptors. In conclusion, these data suggest that the reduction of Ca(2+) influx via VSCCs caused by the activation of P2Y(1) receptors by ATP is the possible mechanism for the inhibition of LTD in prefrontal cortex.
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PMID:P2Y1 receptors inhibit long-term depression in the prefrontal cortex. 2057 Jun 83

Investigations of the cellular substrate for cerebellar learning have focused largely on a single form of plasticity, kinase-dependent long-term depression (LTD). In this issue of Neuron, Schonewille et al. provide evidence that calcineurin, a protein phosphatase required for long-term potentiation (LTP) and other cellular processes, may be just as important.
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PMID:Phosphatase activity controls the ups and downs of cerebellar learning. 2079 38

Evidence shows that the serine/threonine protein phosphatase 1 (PP1) plays a critical role in synaptic plasticity and memory. Little is known about the contribution of the serine/threonine phosphatase 1 (PP2A) to synaptic plasticity. Both protein phosphatases can target the transcription factor cAMP response element binding protein (CREB), whose phosphorylation at Ser133, we previously found, was downregulated during long-term depression (LTD) of glutamatergic transmission in area CA1 of the adult hippocampus in vivo. Other work from our group showed that the activity of PP2A, as well as that of PP1, is increased after LTD induction in area CA1 in vivo. We therefore investigated here whether both protein phosphatases are necessary for LTD in area CA1, and whether they both are involved in the LTD-associated modification of CREB. We found that inhibition of either PP1 or PP2A interferes with the establishment of LTD. Furthermore, inhibition of either enzyme alone abrogated the LTD-associated dephosphorylation of CREB. Interestingly, inhibition of PP1 disrupted CREB dephosphosphorylation rapidly after LTD-inducing stimulation, whereas inhibition of PP2A did not blunt the CREB modification until a later time point. Thus, both PP1 and PP2A regulate CREB during LTD in area CA1, although possibly through different signaling pathways. Our results demonstrate that PP2A, similar to PP1, plays an essential role in the molecular events that underlie LTD at glutamatergic synapses in hippocampal area CA1 in vivo. We propose that one of the mechanisms through which these protein phosphatases may contribute to the prolonged maintenance of LTD is through the regulation of CREB.
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PMID:Protein phosphatases 1 and 2A are both required for long-term depression and associated dephosphorylation of cAMP response element binding protein in hippocampal area CA1 in vivo. 2082 29


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