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: EC:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Methamphetamine [METH ("speed")] is an abused psychostimulant that can cause psychotic, cognitive, and psychomotor impairment in humans. These signs and symptoms are thought to be related to dysfunctions in basal ganglionic structures of the brain. To identify possible molecular bases for these clinical manifestations, we first used cDNA microarray technology to measure METH-induced transcriptional responses in the striatum of rats treated with an apoptosis-inducing dose of the drug. METH injection resulted in increased expression of members of the Jun, Egr, and Nur77 subfamilies of transcription factors (TFs), changes that were confirmed by quantitative PCR. Because pathways linked to these factors are involved in the up-regulation of Fas ligand (FasL), FasL mRNA was quantified and found to be increased. Immunohistochemical studies also revealed METH-induced increased FasL protein expression in striatal GABAergic neurons that express enkephalin. Moreover, there were METH-mediated increases in calcineurin, as well as shuttling of nuclear factor of activated T cells (NFAT)c3 and NFATc4 from the cytosol to the nucleus of METH-treated rats, mechanisms also known to be involved in FasL regulation. Furthermore, METH induced cleavage of caspase-3 in FasL- and Fas-containing neurons. Finally, the METH-induced changes in the FasL-Fas death pathway were attenuated by pretreatment with the dopamine D1 receptor antagonist, SCH23390, which also caused attenuation of METH-induced apoptosis. These observations indicate that METH causes some of its neurodegenerative effects, in part, via stimulation of the Fas-mediated cell death pathway consequent to FasL up-regulation mediated by activation of multiple TFs.
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PMID:Calcineurin/NFAT-induced up-regulation of the Fas ligand/Fas death pathway is involved in methamphetamine-induced neuronal apoptosis. 1564 46

Increased osteoclastic resorption and subsequent bone loss are common features of many debilitating diseases including osteoporosis, bone metastases, Paget's disease, and rheumatoid arthritis. While rapid progress has been made in elucidating the signaling pathways directing osteoclast differentiation and function, a comprehensive picture is far from complete. Here, we explore the role of the Ca(2+)-activated regulator calmodulin in osteoclastic differentiation, functional bone resorption, and apoptosis. During active bone resorption, calmodulin expression is increased, and calmodulin concentrates at the ruffled border, the organelle utilized for acid transport and bone dissolution. Pharmacologic inhibitors of calmodulin, several of which are already used clinically as anti-cancer and anti-psychotic agents, inhibit osteoclastic acid transport, suggesting their potential as bone-sparing drugs. Recent studies also implicate calmodulin in osteoclast apoptosis through a mechanism involving its direct interaction with the death receptor Fas. During osteoclastogenesis, RANKL-induction stimulates a rise in intracellular Ca2+, which in turn activates calmodulin and its downstream effectors. In particular, the Ca(2+)/calmodulin-dependent phosphatase calcineurin and its targets, the NFAT family of transcription factors, have been posited as the master regulators of osteoclastogenesis. However, recent in vivo and in vitro studies demonstrate that another Ca(2+)/calmodulin-regulated effector protein, CaMKII, is also involved. CaMKII(+/-) mutant mice have reduced osteoclast numbers, and CaMKII antagonists inhibit osteoclastogenesis in vitro. Furthermore, CaMKII is known to activate AP-1 transcription factors, which are also required for RANKL-induced osteoclast gene transcription, and recent findings suggest that CaMKII can down-regulate gp130, a cytokine receptor involved in bone remodeling and implicated in numerous osteo-articular diseases.
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PMID:Calmodulin is a critical regulator of osteoclastic differentiation, function, and survival. 1621 8

We used okadaic acid (OA), a potent preferential inhibitor of PP2A and PP5 but not PP1 (PP subfamilies), to examine the involvement of serine/threonine protein phosphatase (PP) in behavioral sensitization stimulated by treatment with cocaine in mice. Repeated administration of cocaine (10 mg kg(-1)) once a day for five consecutive days produced a progressive increase in locomotor activity that was maintained after the cessation of cocaine treatment, as revealed by the fact that a challenge dose of cocaine given on day 7 of withdrawal reproduced an enhanced stimulant effect. On the seventh day of withdrawal, OA-sensitive PP activity and expression of PP2A and PP5, but not PP1gamma, were increased in whole-cell extract of the nucleus accumbens and the ventral tegmental area in cocaine-sensitized mice, compared to saline-treated mice. Restraint stress increased locomotor activity in cocaine-sensitized mice on day 7 after drug administration was ceased. The locomotor activity was more susceptible to restraint-elicited enhancement in cocaine-sensitized mice than in saline-treated mice. The restraint-induced hyperlocomotion was suppressed by a single intracerebroventricular injection of OA immediately before restraint in cocaine-sensitized mice, but this suppression did not occur in saline-treated mice. The membrane fraction of the whole brain in cocaine-sensitized mice showed that OA-sensitive activity levels rise after mice are subjected to restraint, and this is concomitant with an increase in expression levels of PP2A and PP5, but not PP1gamma. These results suggest that the upregulated OA-sensitive PPs are involved in stress-induced hyperlocomotion in cocaine-sensitized mice. There may be intracellular mechanisms mediating psychostimulant cross-sensitization to stress underlying the spontaneous recurrence of its psychosis.
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PMID:Involvement of serine/threonine protein phosphatases sensitive to okadaic acid in restraint stress-induced hyperlocomotion in cocaine-sensitized mice. 1668 59

In humans, phencyclidine (PCP), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, reproduces a schizophrenia-like psychosis including positive symptoms, negative symptoms and cognitive dysfunction. Thus, PCP-treated animals have been utilized as an animal model of schizophrenia. PCP-treated animals exhibit hyperlocomotion as an index of positive symptoms, and a social behavioral deficit in a social interaction test and enhanced immobility in a forced swimming test as indices of negative symptoms. They also show a sensorimotor gating deficit and cognitive dysfunctions in several learning and memory tests. Some of these behavioral changes endure after withdrawal from repeated PCP treatment. Furthermore, repeated PCP treatment induces some neurochemical and neuronanatomical changes. Recently, genetic approaches based on "the glutamate hypothesis of schizophrenia" have been used to develop animal models of schizophrenia. NMDA receptor subunit zeta1 knockdown, epsilon1 knockout (KO) and zeta1 point mutant mice exhibiting a hypofunction of NMDA receptors show hyperlocomotion, social behavioral deficit, sensorimotor gating deficit or cognitive dysfunction. Forebrain-specific calcineurin KO, neuregulin 1 heterozygous KO and lysophosphatidic acid 1 receptor KO mice can also serve as animal models of schizophrenia. These findings suggest that PCP and genetic animal models would be useful for evaluating novel therapeutic candidates and for confirming pathological mechanisms of schizophrenia.
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PMID:Phencyclidine and genetic animal models of schizophrenia developed in relation to the glutamate hypothesis. 1760 43

Chronic treatment of antipsychotic drugs can modulate gene expression in the brain, which may underscore their clinical efficacy. Aripiprazole is the first approved antipsychotic drug of the class of dopamine D2 receptor partial agonist, which has been shown to have similar efficacy and favourable side-effects profile compared to other antipsychotic drugs. This study aimed to identify differential gene expression induced by chronic treatment of aripiprazole. We used microarray-based gene expression profiling technology, real-time quantitative PCR and Western blot analysis to identify differentially expressed genes in the frontal cortex of rats under 4 wk treatment of aripiprazole (10 mg/kg). We were able to detect ten up-regulated genes, including early growth response gene 1, 2, 4 (Egr1, Egr2, Egr4), chromobox homolog 7 (Cbx7), cannabinoid receptor (Cnr1), catechol-O-methyltransferase (Comt), protein phosphatase 2c, magnesium dependent (Ppm2c), tachykinin receptor 3 (Tacr3), Wiscott-Aldrich syndrome-like gene (Wasl) and DNA methyltransferase 3a (Dnmt3a). Our data indicate that chronic administration of aripiprazole can induce differential expression of genes involved in transcriptional regulation and chromatin remodelling and genes implicated in the pathogenesis of psychosis.
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PMID:Chronic treatment with aripiprazole induces differential gene expression in the rat frontal cortex. 1786 1

Chronic administration of antipsychotic drugs produces adaptive responses at the cellular and molecular levels that may be responsible for both the main therapeutic effects and rebound psychosis, which is often observed upon discontinuation of these drugs. Here we show that some antipsychotic drugs produce significant functional changes in serotonergic neurons that directly impact feeding behavior in the model organism, Caenorhabditis elegans. In particular, antipsychotic drugs acutely suppress pharyngeal pumping, which is regulated by serotonin from the NSM neurons. By contrast, withdrawal from food and drug is accompanied by a striking recovery and overshoot in the rate of pharyngeal pumping. This rebound response is absent or diminished in mutant strains that lack tryptophan hydroxylase (TPH-1) or the serotonin receptors SER-7 and SER-1, and is blocked by serotonin antagonists, which implicates serotonergic mechanisms in this adaptive response. Consistent with this, continuous drug exposure stimulates an increase in serotonin and the number of varicosities along the NSM processes. Cyclosporin A and calcineurin mutant strains mimic the effects of the antipsychotic drugs and reveal a potential role for the calmodulin-calcineurin signaling pathway in the response of serotonergic neurons. Similar molecular and cellular changes may contribute to the long-term adaptive response to antipsychotic drugs in patients.
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PMID:Behavioral adaptation in C. elegans produced by antipsychotic drugs requires serotonin and is associated with calcium signaling and calcineurin inhibition. 1944 97

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 molecular modes of action of antipsychotic drugs are poorly understood beyond their effects at the dopamine D2 receptor. Previous studies have placed Akt signaling downstream of D2 dopamine receptors, and recent data have suggested an association between psychotic illnesses and defective Akt signaling. To characterize the effect of antipsychotic drugs on the Akt pathway, we used the model organism C. elegans, a simple system where the Akt/forkhead box O transcription factor (FOXO) pathway has been well characterized. All major classes of antipsychotic drugs increased signaling through the insulin/Akt/FOXO pathway, whereas four other drugs that are known to affect the central nervous system did not. The antipsychotic drugs inhibited dauer formation, dauer recovery, and shortened lifespan, three biological processes affected by Akt signaling. Genetic analysis showed that AKT-1 and the insulin and insulin-like growth factor receptor, DAF-2, were required for the antipsychotic drugs to increase signaling. Serotonin synthesis was partially involved, whereas the mitogen activated protein kinase (MAPK), SEK-1 is a MAP kinase kinase (MAPKK), and calcineurin were not involved. This is the first example of a common but specific molecular effect produced by all presently known antipsychotic drugs in any biological system. Because untreated schizophrenics have been reported to have low levels of Akt signaling, increased Akt signaling might contribute to the therapeutic actions of antipsychotic drugs.
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PMID:Antipsychotic drugs activate the C. elegans akt pathway via the DAF-2 insulin/IGF-1 receptor. 2277 38

Depression affects up to 60% of solid-organ recipients and is independently associated with both mortality (hazard ratio for death of ~2) and de novo malignancy after transplantation, although the mechanism is not clear. Both pretransplantation psychosis and depression occurring more than 2 years after transplantation are associated with increased noncompliance and graft loss. It remains to be shown that effective treatment of depression is associated with improved outcomes and quality of life. Immunosuppressive drugs (especially corticosteroids and calcineurin inhibitors) and physiologic challenges can precipitate deterioration in mental health. All potential transplant candidates should be assessed for mental health problems and preexisting medical conditions that can mimic mental health problems, such as uremic, hepatic, or hypoxic encephalopathy, should be identified and treated appropriately. Expert mental health review of those with identified risk factors (such as previous suicide attempts, history of mental illness or noncompliance with medications) is advisable early in the transplant assessment process to mitigate risk and support the patient. Patients with mental health disorders, when adequately controlled and socially supported, have outcomes similar to the general transplant population. Therefore, exclusion from transplantation based on the diagnosis alone is neither ethically nor medically justified. However, it is ethically and clinically justifiable to deny access to transplantation to those who, despite full support, would have a quality of life that is unacceptable to the candidate or are likely to be noncompliant with treatment or follow-up, which would lead to graft loss.
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PMID:Mental health disorders and solid-organ transplant recipients. 2374 26

Repeat administration of psychostimulants, such as methamphetamine, produces a progressive increase in locomotor activity (behavioral sensitization) in rodents that is believed to represent the underlying neurochemical changes driving psychoses. Alterations to the prefrontal cortex (PFC) are suggested to mediate the etiology and maintenance of these behavioral changes. As such, the aim of the current study was to investigate changes to protein expression in the PFC in male rats sensitized to methamphetamine using quantitative label-free shotgun proteomics. A methamphetamine challenge resulted in a significant sensitized locomotor response in methamphetamine pretreated animals compared to saline controls. Proteomic analysis revealed 96 proteins that were differentially expressed in the PFC of methamphetamine treated rats, with 20% of these being previously implicated in the neurobiology of schizophrenia in the PFC. We identified multiple biological functions in the PFC that appear to be commonly altered across methamphetamine-induced sensitization and schizophrenia, and these include synaptic regulation, protein phosphatase signaling, mitochondrial function, and alterations to the inhibitory GABAergic network. These changes could inform how alterations to the PFC could underlie the cognitive and behavioral dysfunction commonly seen across psychoses and places such biological changes as potential mediators in the maintenance of psychosis vulnerability.
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PMID:Methamphetamine-induced sensitization is associated with alterations to the proteome of the prefrontal cortex: implications for the maintenance of psychotic disorders. 2524


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