Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glutamate is the predominant excitatory neurotransmitter in the mammalian central nervous system and is critical for essentially all physiological processes ranging from control of motor and somatosensory function to information processing and storage. Like many other small molecule neurotransmitters, transporters localized to the plasma membrane control the extracellular concentrations of glutamate. These transporters are both acutely and chronically regulated by several different mechanisms that presumably contribute to the protection of the nervous system from hypo- or hyper-glutamatergic function. In this review, we will describe our emerging understanding of one aspect of glutamate transporter regulation that is dependent on protein kinase C. More than a decade of extensive research on glutamate receptor-specific therapeutics has been driven by the hypothesis that these agents might be useful for pain management, treatment of schizophrenia or other psychiatric disorders, and prevention of neurodegenerative diseases. We assume that, in this modern era of drug discovery, understanding the endogenous regulatory mechanisms that are activated under physiological and pathological conditions will be required before one can target transporters for a ubiquitous neurotransmitter like glutamate.
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PMID:Protein kinase C-dependent remodeling of glutamate transporter function. 1499 76

The neuronal transporters for the monoamines dopamine, serotonin, and norepinephrine are plasma membrane proteins that serve vital functions in the reuptake and control of synaptic neurotransmitter levels. They are also targets for abused and therapeutic drugs and play pivotal roles in neurological disorders such as depression, schizophrenia, and Parkinson's disease. There is increasing evidence that some activities of these carriers are subject to acute control by treatments that affect phosphorylation pathways, but the molecular basis for this is not understood. Recent work suggests that these regulatory processes may involve phosphorylation of the transporters by protein kinase C and other kinases, and may occur by affecting intrinsic transport activity or by controlling transporter cell surface expression. Phosphorylation-mediated regulation of monoamine transporters provides the potential for acute presynaptic control of neurotransmitter levels during normal neurophysiologic events, and dysregulation of these processes may lead to inappropriate transmitter clearance that contributes to the etiology of neurological disorders.
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PMID:Phosphorylation and regulation of psychostimulant-sensitive neurotransmitter transporters. 1506 32

Dietary fat has a dual role in human physiology: a) it functions as a source of energy and structural components for cells; b) it functions as a regulator of gene expression that impacts lipid, carbohydrate, and protein metabolism, as well as cell growth and differentiation. Fatty acid effects on gene expression are cell-specific and influenced by fatty acid structure and metabolism. Fatty acids interact with the genome through several mechanisms. They regulate the activity or nuclear abundance of several transcription factors, including PPAR, LXR, HNF-4, NFkappaB, and SREBP. Fatty acids or their metabolites bind directly to specific transcription factors to regulate gene transcription. Alternatively, fatty acids indirectly act on gene expression through their effects on a) specific enzyme-mediated pathways, such as cyclooxygenase, lipoxygenase, protein kinase C, or sphingomyelinase signal transduction pathways; or b) pathways that involve changes in membrane lipid/lipid raft composition that affect G-protein receptor or tyrosine kinase-linked receptor signaling. Further definition of these fatty acid-regulated pathways will provide insight into the role dietary fat plays in human health and the onset and progression of several chronic diseases, like coronary artery disease and atherosclerosis, dyslipidemia and inflammation, obesity and diabetes, cancer, major depressive disorders, and schizophrenia.
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PMID:Fatty acid regulation of gene transcription. 1507 23

A "partial" rodent model for schizophrenia has been used to characterize the regulation of hippocampal genes in response to amygdalar activation. At 96 h after the administration of picrotoxin into the basolateral nucleus, we have observed an increase in the expression of genes associated with 18 different monoamine (ie adrenergic alpha 1, alpha 2 and beta 2, serotonergic 5HT5b and 5HT6, dopamine D4 and muscarinic m1, m2 and m3) and peptide (CCK A and B, angiotensin 1A, mu and kappa opiate, FSH, TSH, LH, GNRH, and neuropeptide Y) G-protein coupled receptors (GPCRs). These latter receptors are associated with three different G protein signaling pathways (Gq, Gs, and Gi) in which significant changes in gene expression were also noted for adenylate cyclase (AC4), phosphodiesterase (PDE4D), protein kinase A (PKA), and protein kinase C (PKC). Quantitative RT-PCR was used to validate the results and demonstrated that there were predictable increases of three GPCRs selected for this analysis, including the dopamine D4, alpha 1b, and CCK-B receptors. Eight out of the nine monoamine receptors showing these changes have moderate to high affinity for the atypical antipsychotic, clozapine. Taken together, these results suggest that amygdalar activation may play a role in the pathophysiology and treatment of psychosis by regulating the activity of multiple GPCR and metabolic pathways in hippocampal cells.
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PMID:Acute amygdalar activation induces an upregulation of multiple monoamine G protein coupled pathways in rat hippocampus. 1517 Apr 62

The discovery of lithium's efficacy as a mood-stabilizing agent revolutionized the treatment of patients with bipolar disorder and after 5 decades this drug continues to be the mainstay of treatment of this disorder. Valproate, which is dissimilar structurally to lithium, shares most of the effects of lithium at the level of protein kinase C (PKC). Both drugs reduce the activity of PKC, though via different mechanisms. In comparison to patients with major depressive disorder, schizophrenia, or healthy controls, PKC activity is significantly elevated in manic patients, suggesting that changes of PKC activity may be a central pathological trait of the illness. The precise physiological role of PKC activity in the regulation of mood is unclear. The enzyme modulates cellular responses via phosphorylation of numerous substrate proteins. Such substrates of PKC include cytoskeletal proteins, neurotransmitter and hormone receptors, G proteins, GAP-43, MARCKS etc. Further studies are required to clarify any causal role of CPK changes in bipolar-disorder.
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PMID:[On the relevance of protein kinase C to lithium therapy in bipolar disorder]. 1552 99

Clozapine is an atypical antipsychotic that has a unique clinical profile that distinguishes it from other typical and atypical antipsychotics. At present, the underlying mechanisms of action of clozapine are unclear. Recent studies in the field of schizophrenia suggest that compounds that potentiate N-methyl-d-aspartate (NMDA) receptor function in the appropriate brain regions might be an effective antipsychotic agent. One relevant region in which NMDA receptors play a key role in mediating neurotransmission is the nucleus accumbens. Therefore, we investigated the regulation of NMDA receptor currents and excitatory postsynaptic currents (EPSCs) by clozapine in nucleus accumbens neurons. Whole-cell patch-clamp recordings were performed in rat brain slices. We demonstrate that bath application of clozapine but not haloperidol or the selective 5-hydroxytryptamine 2A antagonist MDL100907 [(R)-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluoro-phenyl)ethyl]-4-piperidine methanol] induces a robust potentiation of NMDA-evoked currents and of glutamatergic EPSCs and that this potentiation is dependent on dopamine release and postsynaptic activation of D1 receptors. Furthermore, the effect of clozapine is selective for NR2B subtype-containing NMDA receptors and is blocked by the selective Src family kinase inhibitor PP2 [4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine] and the protein kinase A-selective inhibitor N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide but not by the protein kinase C-selective inhibitor bisindolylmaleimide I. This effect of clozapine in the nucleus accumbens might underlie the unique clinical profile of this atypical antipsychotic and provides a basis for novel treatment approaches.
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PMID:Clozapine potentiation of N-methyl-D-aspartate receptor currents in the nucleus accumbens: role of NR2B and protein kinase A/Src kinases. 1565 39

Serotonin 5-HT2C receptors (5-HT(2C)Rs) are almost exclusively expressed in the CNS, and implicated in disorders such as obesity, depression, and schizophrenia. The present study investigated the mechanisms governing the coupling of the 5-HT(2C)R to the extracellular signal-regulated kinases (ERKs) 1/2, using a Chinese hamster ovary (CHO) cell line stably expressing the receptor at levels comparable to those found in the brain. Using the non-RNA-edited isoform of the 5-HT(2C)R, constitutive ERK1/2 phosphorylation was observed and found to be modulated by full, partial and inverse agonists. Interestingly, agonist-directed trafficking of receptor stimulus was also observed when comparing effects on phosphoinositide accumulation and intracellular Ca2+ elevation to ERK1/2 phosphorylation, whereby the agonists, [+/-]-2,5-dimethoxy-4-iodoamphetamine (DOI) and quipazine, showed reversal of efficacy between the phosphoinositide/Ca2+ pathways, on the one hand, and the ERK1/2 pathway on the other. Subsequent molecular characterization found that 5-HT-stimulated ERK1/2 phosphorylation in this cellular background requires phospholipase D, protein kinase C, and activation of the Raf/MEK/ERK module, but is independent of both receptor- and non-receptor tyrosine kinases, phospholipase C, phosphoinositide 3-kinase, and endocytosis. Our findings underscore the potential for exploiting pathway-selective receptor states in the differential modulation of signaling pathways that play prominent roles in normal and abnormal neuronal signaling.
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PMID:Characterization of serotonin 5-HT2C receptor signaling to extracellular signal-regulated kinases 1 and 2. 1593 77

The NR4A1-3 (Nur77, NURR1 and NOR-1) subfamily of nuclear hormone receptors (NRs) has been implicated in Parkinson's disease, schizophrenia, manic depression, atherogenesis, Alzheimer's disease, rheumatoid arthritis, cancer and apoptosis. This has driven investigations into the mechanism of action, and the identification of small molecule regulators, that may provide the platform for pharmaceutical and therapeutic exploitation. Recently, we found that the purine antimetabolite 6-Mercaptopurine (6-MP), which is widely used as an anti-neoplastic and anti-inflammatory drug, modulated the NR4A1-3 subfamily. Interestingly, the agonist-mediated activation did not involve modulation of primary coactivators' (e.g. p300 and SRC-2/GRIP-1) activity and/or recruitment. However, the role of the subsequently recruited coactivators, for example CARM-1 and TRAP220, in 6-MP-mediated activation of the NR4A1-3 subfamily remains obscure. In this study we demonstrate that 6-MP modulates the activity of the coactivator TRAP220 in a dose-dependent manner. Moreover, we demonstrate that TRAP220 potentiates NOR-1-mediated transactivation, and interacts with the NR4A1-3 subgroup in an AF-1-dependent manner in a cellular context. The region of TRAP220 that mediated 6-MP activation and NR4A interaction was delimited to amino acids 1-800, and operates independently of the critical PKC and PKA phosphorylation sites. Interestingly, TRAP220 expression does not increase the relative induction by 6-MP, however the absolute level of NOR-1-mediated trans-activation is increased. This study demonstrates that 6-MP modulates the activity of the NR4A subgroup, and the coactivator TRAP220.
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PMID:TRAP220 is modulated by the antineoplastic agent 6-Mercaptopurine, and mediates the activation of the NR4A subgroup of nuclear receptors. 1595 51

We previously reported that expression level of LIM (ENH, PDLIM5) was significantly and commonly increased in the brains of patients with bipolar disorder, schizophrenia, and major depression. Expression of LIM was decreased in the lymphoblastoid cells derived from patients with bipolar disorders and schizophrenia. LIM protein reportedly plays an important role in linking protein kinase C with calcium channel. These findings suggested the role of LIM in the pathophysiology of bipolar disorder and schizophrenia. To further investigate the role of LIM in these mental disorders, we performed a replication study of gene expression analysis and performed genetic association studies. Upregulation of LIM was confirmed in the independent sample set obtained from Stanley Array Collection. No effect of sample pH or medication was observed. Genetic association study revealed the association of single nucleotide polymorphism (SNP)1 (rs10008257) with bipolar disorder. In an independent sample set, SNP2 (rs2433320) close to SNP1 was associated with bipolar disorder. In total samples, haplotype of these two SNPs was associated with bipolar disorder. No association was observed in case-control analysis and family-based association analysis in schizophrenia. These results suggest that SNPs in the upstream region of LIM may confer the genetic risk for bipolar disorder.
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PMID:Gene expression and association analyses of LIM (PDLIM5) in bipolar disorder and schizophrenia. 1604 70

Dysregulated protein kinase C (PKC) distribution and activation, and abnormal receptor-G protein coupling, have been implicated in the pathophysiology of bipolar affective disorder (BD). The therapeutic effectiveness of lithium has also been correlated with its ability to reduce PKC activation and G protein-mediated signaling. We examine the cellular distribution and activation of PKC and receptor-G protein coupling in blood platelets from normal controls, patients with BD mania or schizophrenia during treatment-free state, and after lithium or valproic acid administration. PKC activity was measured under basal and 50 nM phorbol 12-myristate, 13-acetate (PMA), 1 microM serotonin or 0.5 U/ml thrombin-stimulated conditions. The coupling of G proteins to serotonin or thrombin receptors were assessed by serotonin or thrombin-mediated [35S]GTPgammaS binding to membrane Galpha proteins. The results demonstrate that membrane-associated PKC activity and stimulus-induced PKC translocation are increased in BD manic, whereas stimulus-elicited PKC translocation is attenuated in schizophrenic patients. Lithium and valproic acid treatments attenuated the stimulus-induced PKC translocations to a similar degree and decreased PKC activity in both cytosolic and membranous fractions after two weeks of drug administration. An increase in 5-HT or thrombin stimulated [35S]GTPgammaS binding to Galpha proteins was detected in BD manic but not in schizophrenic patients although basal [35S]GTPgammaS binding was not different across the diagnostic groups. Lithium and valproic acid treatments similarly reduced receptor-G protein coupling with comparable time courses. Thus, increased membrane-associated PKC, cytosol to membrane PKC translocation and receptor-G protein coupling in platelets of BD manic patients were alleviated by lithium or valproic acid treatments.
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PMID:Lithium and valproic acid treatments reduce PKC activation and receptor-G protein coupling in platelets of bipolar manic patients. 1604 35


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