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

As compared to normal people, the lymphocytes of patients with schizophrenia were found to have an impairment of ATP.Mg-dependent protein phosphatase activation. More importantly, the impaired protein phosphatase activation in the lymphocytes of schizophrenic patients could be consistently and completely restored to normal by exogenous pure protein kinase FA/glycogen synthase kinase-3 alpha (kinase FA/GSK-3 alpha) (the activating factor of ATP.Mg-dependent protein phosphatase), indicating that the molecular mechanism for the impaired protein phosphatase activation in schizophrenic patients may be due to a functional loss of kinase FA/GSK-3 alpha. Immunoblotting and kinase activity analysis in an anti-kinase FA/GSK-3 alpha immunoprecipitate further demonstrate that both cellular activities and protein levels of kinase FA/GSK-3 alpha in the lymphocytes of schizophrenic patients were greatly impared as compared to normal controls. Statistical analysis revealed that the lymphocytes isolated from 37 normal people contain kinase FA/GSK-3 alpha activity in the high levels of 14.8 +/- 2.4 units/mg of cell protein, whereas the lymphocytes of 48 patients with schizophrenic disorder contain kinase FA/GSK-3 alpha activity in the low levels of 2.8 +/- 1.6 units/mg, indicating that the different levels of kinase FA/GSK-3 alpha activity between schizophrenic patients and normal people are statistically significant. Taken together, the results provide initial evidence that patients with schizophrenic disorder may have a common impairment in the protein levels and cellular activities of kinase FA/GSK-3 alpha, a multisubstrate protein kinase and a multisubstrate protein phosphatase activator in their lymphocytes.
 ...
PMID:Dysfunction of protein kinase FA/GSK-3 alpha in lymphocytes of patients with schizophrenic disorder. 853 May 29

Signaling through D2 class dopamine receptors is crucial to correct brain development and function, and dysfunction of this system is implicated in major neurological disorders such as Parkinson's disease and schizophrenia. To investigate potential novel mechanisms of D2 receptor regulation, the third cytoplasmic loop of the D2 dopamine receptor was used to screen a rat hippocampal yeast two-hybrid library. Spinophilin, a recently characterized F-actin and protein phosphatase-1-binding protein with a single PDZ domain was identified as a protein that specifically associates with this region of D2 receptors. A direct interaction between spinophilin and the D2 receptor was confirmed in vitro using recombinant fusion proteins. The portion of spinophilin responsible for interacting with the D2 third cytoplasmic loop was narrowed to a region that does not include the actin-binding domain, the PDZ domain, or the coiled-coil. This region is distinct from the site of interaction with protein phosphatase-1, and both D2 receptors and protein phosphatase-1 may bind spinophilin at the same time. The interaction is not mediated via the unique 29-amino acid insert in D2long; both D2long and D2short third cytoplasmic loops interact with spinophilin in vitro and in yeast two-hybrid assays. Expression of D2 receptors containing an extracellular hemagglutinin epitope in Madin-Darby canine kidney cells results in co-localization of receptor and endogenous spinophilin as determined by immunocytochemistry using antibodies directed against spinophilin and the HA tag. We hypothesize that spinophilin is important for establishing a signaling complex for dopaminergic neurotransmission through D2 receptors by linking receptors to downstream signaling molecules and the actin cytoskeleton.
 ...
PMID:Association of the D2 dopamine receptor third cytoplasmic loop with spinophilin, a protein phosphatase-1-interacting protein. 1039 35

The three Nobel laureates Arvid Carlsson, Paul Greengard and Eric Kandel have made pioneering discoveries concerning slow synaptic transmission between neurons. As common theme, for which the Nobel Prize in Physiology or Medicine for 2000 is given, the Nobel Assembly chose 'signal transduction in the nervous system'. The work of Carlsson led to the discovery of dopamine as transmitter in the brain and opened the way for the development of the levodopa therapy of patients suffering from Parkinson's disease. His later work concentrated on the dopamine hypothesis of schizophrenia and the rationale for the mechanism of action of antipsychotics. Greengard pioneered the field of receptor-mediated phosphorylation and dephosphorylation of brain proteins. He was the first to describe the cyclic-AMP-dependent protein kinase in the brain and the activation of this kinase following dopamine receptor activation. A substrate enriched in cells that bear dopamine receptors is 'dopamine- and cyclic-AMP-regulated phosphoprotein' (DARPP-32). Phosphorylation by the cyclic-AMP-dependent kinase influences its protein phosphatase inhibiting capacity and, as such, DARPP-32 is an important 'feed-forward activator' in the dopamine signal transduction cascade. Kandel received the prize for his contributions to our understanding of the neural substrate of learning and memory. Most of his work was carried out in the sea slug Aplysia in which he was able to relate three psychologically defined forms of learning--habituation, sensitisation, and classical conditioning--to subcellular processes and intercellular signalling. Kandel is known all over the world for his eminent textbook Principles of Neural Science which inspired generations of young neuroscientists. It seems that it is not so much the signal transduction that joins these laureates but their outstanding conceptual approach to, in fact, three different themes of the neurosciences during the second part of the last century.
 ...
PMID:[Nobel prize in physiology of medicine for year 2000 for research of signal transduction in the nervous system]. 1110 53

There is growing evidence linking alterations in serotonergic signaling in the prefrontal cortex to the etiology of schizophrenia. Prefrontal pyramidal neurons are richly innervated by serotonergic fibers and express high levels of serotonergic 5-HT(2)-class receptors. It is unclear, however, how activation of these receptors modulates cellular activity. To help fill this gap, whole cell voltage-clamp and single-cell RT-PCR studies of acutely isolated layer V-VI prefrontal pyramidal neurons were undertaken. The vast majority (>80%) of these neurons had detectable levels of 5-HT(2A) or 5-HT(2C) receptor mRNA. Bath application of 5-HT(2) agonists inhibited voltage-dependent Ca(2+) channel currents. L-type Ca(2+) channels were a particularly prominent target of this signaling pathway. The L-type channel modulation was blocked by disruption of G(alphaq) signaling or by inhibition of phospholipase Cbeta. Antagonism of intracellular inositol trisphosphate signaling, chelation of intracellular Ca(2+), or depletion of intracellular Ca(2+) stores also blocked this modulation. Inhibition of the Ca(2+)-dependent phosphatase calcineurin prevented receptor-mediated modulation of L-type currents. Last, the 5-HT(2) receptor modulation was robustly expressed in neurons from Ca(v)1.3 knockout mice. These findings argue that 5-HT(2) receptors couple through G(alphaq) proteins to trigger a phospholipase Cbeta/inositol trisphosphate signaling cascade resulting in the mobilization of intracellular Ca(2+), activation of calcineurin, and inhibition of Ca(v)1.2 L-type Ca(2+) currents. This modulation and its blockade by atypical neuroleptics could have wide-ranging effects on synaptic integration and long-term gene expression in deep-layer prefrontal pyramidal neurons.
 ...
PMID:Stimulation of 5-HT(2) receptors in prefrontal pyramidal neurons inhibits Ca(v)1.2 L type Ca(2+) currents via a PLCbeta/IP3/calcineurin signaling cascade. 1197 86

The dopamine (DA) innervation of medial prefrontal cortex (mPFC) regulates cognitive activity in a complex manner. Alterations of DA function, particularly via the DA D1 receptor class (D1R), are implicated in both schizophrenia and drug addiction, yet the precise roles of DA in modulating mPFC excitability remain unclear. We focused on DA modulation of voltage-gated K(+) current (VGKC) in acutely dissociated rat mPFC pyramidal neurons. We defined three components of the whole-cell VGKC according to biophysical and pharmacological properties. The A-type current (I(A)), with rapid activation and inactivation kinetics, was completely inactivated by prolonged holding of the membrane potential at -40 mV and was sensitive to the K(+) channel blocker 4-aminopyridine (4-AP) but not tetraethylammonium (TEA) or dendrotoxin (DTX). The slowly inactivating K(+) current (I(D)), with rapid activation but relatively slow inactivation, was the major contributor to VGKC and was completely inactivated at -40 mV and sensitive to TEA and DTX but less so to 4-AP. The very slowly inactivating K(+) current (I(K)) was elicited by command steps to more depolarized potentials from a prolonged holding potential of -40 mV and was sensitive to all three blockers. Stimulation of DA D2 receptors failed to alter any component of whole-cell VGKC. Stimulation of DA D1Rs selectively suppressed I(D), an effect mimicked by the adenylyl cyclase activator forskolin, the active cAMP analog Sp-cAMP, and the protein phosphatase inhibitor okadaic acid. Inhibition of protein kinase A (PKA) with either PKI or Rp-cAMP abolished D1R modulation. Thus, the DA D1R/cAMP/PKA signaling pathway mediates modulation of I(D) by DA in rat mPFC pyramidal neurons.
 ...
PMID:Dopamine D1-class receptors selectively modulate a slowly inactivating potassium current in rat medial prefrontal cortex pyramidal neurons. 1268 54

Calcineurin (CN), a calcium- and calmodulin-dependent protein phosphatase, plays a significant role in the central nervous system. Previously, we reported that forebrain-specific CN knockout mice (CN mutant mice) have impaired working memory. To further analyze the behavioral effects of CN deficiency, we subjected CN mutant mice to a comprehensive behavioral test battery. Mutant mice showed increased locomotor activity, decreased social interaction, and impairments in prepulse inhibition and latent inhibition. In addition, CN mutant mice displayed an increased response to the locomotor stimulating effects of MK-801. Collectively, the abnormalities of CN mutant mice are strikingly similar to those described for schizophrenia. We propose that alterations affecting CN signaling could comprise a contributing factor in schizophrenia pathogenesis.
 ...
PMID:Conditional calcineurin knockout mice exhibit multiple abnormal behaviors related to schizophrenia. 1285 57

Schizophrenia is a severe psychiatric disorder characterized by a complex mode of inheritance. Forebrain-specific CNB knockout mice display a spectrum of behavioral abnormalities related to altered behaviors observed in schizophrenia patients. To examine whether calcineurin dysfunction is involved in schizophrenia etiology, we undertook studies of an initial subset of calcineurin-related genes, prioritizing ones that map to loci previously implicated in schizophrenia by linkage studies. Transmission disequilibrium studies in a large sample of affected families detected association of the PPP3CC gene, which encodes the calcineurin gamma catalytic subunit, with disease. Our results identify PPP3CC, located at 8p21.3, as a potential schizophrenia susceptibility gene and support the proposal that alterations in calcineurin signaling contribute to schizophrenia pathogenesis.
 ...
PMID:Evidence for association of schizophrenia with genetic variation in the 8p21.3 gene, PPP3CC, encoding the calcineurin gamma subunit. 1285 58

Although psychiatric diseases are among the most common and destructive of all human illnesses, the molecular and cellular mechanisms underlying their complex origins remain to be elucidated. Dysfunction of critical intracellular signaling pathways is very likely to be involved. This conclusion is based on a number of observations, including the short- and long-term cellular effects of psychiatric drugs; the critical role signaling pathways play in neurotransmitter, neuropeptide, and neurohormone communication; and the fact that signaling pathways are principle regulators of the diverse array of behavioral symptoms experienced by patients. The genomics era has brought to psychiatry an abundance of genetic linkage and candidate gene findings. The difficult task--now under way--is to discern the functional relevance of these results. Recent evidence suggests the involvement of the ubiquitous protein phosphatase 2B (calcineurin), a critical regulator of many signal transduction pathways, as a schizophrenia susceptibility gene. It is likely that genetic findings in severe psychiatric disorders will continue to implicate direct and indirect modulation of critical intracellular signaling pathways.
 ...
PMID:Signal transduction and genes-to-behaviors pathways in psychiatric diseases. 1460 Feb 93

Three distinct classes of drugs: dopaminergic agonists (such as D-amphetamine), serotonergic agonists (such as LSD), and glutamatergic antagonists (such as PCP) all induce psychotomimetic states in experimental animals that closely resemble schizophrenia symptoms in humans. Here we implicate a common signaling pathway in mediating these effects. In this pathway, dopamine- and an adenosine 3',5'-monophosphate (cAMP)-regulated phospho-protein of 32 kilodaltons (DARPP-32) is phosphorylated or dephosphorylated at three sites, in a pattern predicted to cause a synergistic inhibition of protein phosphatase-1 and concomitant regulation of its downstream effector proteins glycogen synthesis kinase-3 (GSK-3), cAMP response element-binding protein (CREB), and c-Fos. In mice with a genetic deletion of DARPP-32 or with point mutations in phosphorylation sites of DARPP-32, the effects of D-amphetamine, LSD, and PCP on two behavioral parameters-sensorimotor gating and repetitive movements-were strongly attenuated.
 ...
PMID:Diverse psychotomimetics act through a common signaling pathway. 1524 57

Calcineurin, one of the serine/threonine protein phosphatase, comprises more than 1% of the total protein content in brain. This evidence points towards important roles of calcineurin in neural function. Miyakawa et al. reported that forebrain-specific calcineurin knockout mice showed the behavioral abnormalities that are often observed in schizophrenia patients. Based on this evidence, they suggested that calcineurin dysfunction could be involved in schizophrenia pathogenesis. Thereafter this report, Gerber et al. performed transmission disequilibrium test (TDT) studies and showed an evidence for a nominally significant over-transmission of a common haplotype of the human calcineurin A gamma subunit gene (PPP3CC). We performed association analysis of PPP3CC in Japanese sample of 457 schizophrenia cases and 429 controls. To our regret, we could not confirm the association with Japanese schizophrenia to PPP3CC including core at-risk haplotype. Our result suggests that PPP3CC may not play a major role in Japanese schizophrenia.
 ...
PMID:No association with the calcineurin A gamma subunit gene (PPP3CC) haplotype to Japanese schizophrenia. 1584 70


1 2 3 4 5 6 7 Next >>