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  • Enhancement of high threshold calcium currents in rat primary afferent neurons by constitutively active protein kinase C.

    23 July 2018

    Protein kinase C has been implicated in the modulation of calcium channel function. However, controversy exists concerning the actions of agents such as phorbol esters or diacylglycerol (DAG) that activate endogenous PKC, with both enhancement and inhibition of Ca2+ currents described. In this article we report the effects of direct intracellular application of a constitutively active form of PKC (PKM) on whole cell calcium currents in acutely dissociated rat dorsal root ganglion neurons. PKM application significantly enhanced high threshold voltage-activated calcium currents elicited from holding potentials of -80 mV and -40 mV. The rate of current rundown in PKM-treated cells was not significantly different from controls. The enhancement observed with PKM was not due to a shift in the voltage dependence of the peak current. Synthetic PKC inhibitor peptide (PKC-I) added to recording solutions containing PKM (PKM+PKC-I) abolished the PKM-associated enhancement. The rate of current rundown was significantly increased in the presence of PKM+PKC-I, and PKC-I alone, suggesting that substantial enhancement of voltage-activated calcium currents by endogenous PKC occurred in this preparation of rat dorsal root ganglion neurons. The portions of current attributable to N-, L-, and non-N,L-type currents [determined by applying the N- and L-type calcium antagonists omega-conotoxin GVIA and nifedipine (3-10 microM)] were not affected by PKM, suggesting that both N and L current components were enhanced by PKM.(ABSTRACT TRUNCATED AT 250 WORDS)

  • Microwave radiation, in the absence of hyperthermia, has no detectable effect on synapsin I levels or phosphorylation.

    23 July 2018

    Recent reports have indicated that microwave radiation can produce effects on a variety of cell types in vitro. To determine whether microwave radiation might be neurotoxic, the effects of microwave radiation on synapsin I have been examined. Synapsin I is a neuron-specific phosphoprotein that is present in all neurons, where it is localized to the presynaptic terminal and is associated with synaptic vesicles. O'Callaghan and Miller have demonstrated that studies of such neuron-specific proteins can provide reliable indices of neurotoxicity. We have used a radioimmunoassay for synapsin I to determine whether microwave irradiation has any effect on the levels of synapsin I. Neither acute nor chronic exposure to microwave irradiation had any detectable effect on synapsin I levels. We have also examined the calcium-dependent phosphorylation of synapsin I in synaptosomes isolated from rats that had been subjected to microwave radiation. The phosphorylation of synapsin I in synaptosomes reflects numerous components of the presynaptic aspect of neuronal transmission. At intensities below that required to produce mild hyperthermia, no effects of microwave irradiation were seen on synapsin I phosphorylation.

  • Cholinergic regulation of protein III phosphorylation in bovine adrenal chromaffin cells.

    23 July 2018

    Protein IIIa (Mr approximately 74,000) and protein IIIb (Mr approximately 55,000), referred to collectively as protein III, are synaptic vesicle-associated phosphoproteins found in all regions of the rat nervous system and in the rat adrenal medulla. In the present study, the presence of protein III and the regulation of its phosphorylation were examined in chromaffin cells isolated from bovine adrenal medullae. Protein III was present in chromaffin cells isolated and purified from bovine adrenal medullae. The levels of protein III were moderately enriched in purified chromaffin cells compared with whole adrenal medullae. Preincubation of chromaffin cells with 32PO4 led to the endogenous phosphorylation of protein III, and phosphopeptide maps of chromaffin cell protein III were similar to those of protein III from bovine cerebral cortex. Treatment of the chromaffin cells with ACh produced calcium-dependent increases in both the phosphorylation of protein III and the release of 3H-norepinephrine. These effects of ACh were mimicked by nicotine but not by muscarine. Other secretagogues (elevated K+, veratridine, Ba2+) also increased both the phosphorylation of protein III and the release of 3H-norepinephrine. However, detailed characterization of the secretagogue-induced increases in protein III phosphorylation and 3H-norepinephrine secretion suggested that protein III phosphorylation was more directly associated with an increase in intracellular calcium than with secretion per se.

  • Regional and subunit specific changes in NMDA receptor mRNA and immunoreactivity in mouse brain following chronic ethanol ingestion.

    23 July 2018

    Chronic ethanol treatment of mice has been shown to result in increased binding of dizocilpine and glutamate to hippocampal NMDA receptors. These changes were suggested to reflect an increase in NMDA receptor number that may underlie certain signs of the ethanol withdrawal syndrome. However, there was no change in binding of a competitive NMDA receptor antagonist, or of ligand binding to the glycine co-agonist site on the receptor after chronic ethanol treatment. Differential changes in the binding of particular ligands at the NMDA receptor suggested the possibility that chronic ethanol ingestion might selectively affect the expression of particular NMDA receptor subunits. Our current work demonstrates that chronic ethanol ingestion by mice, which results in the generation of physical dependence, also produces increases in the NMDA receptor NR1 subunit protein in the hippocampus and cerebellum (approximately 50% and 95%, respectively), and produces increases in the NR2A subunit protein in the hippocampus and cortex (approximately 25% and 40%, respectively). However, the mRNA levels for these subunits were not increased in the respective brain areas by the same ethanol treatment. The changes in NMDA receptor subunit expression in discrete areas of the brain may contribute to the previously observed changes in ligand binding and, possibly, signs of ethanol withdrawal.

  • Calcium signalling in bovine adrenal chromaffin cells: additive effects of histamine and nicotine.

    23 July 2018

    In a previous report, we described the ability of two secretogogues, histamine and nicotine, to stimulate additive effects on catecholamine (CA) release and synapsin II phosphorylation in bovine adrenal chromaffin cells (BACC) [Firestone and Browning (1992), J. Neurochem., 58:441-447]. We hypothesized that these results were due to the combined effects on cytosolic Ca++ of the two distinct signalling pathways. We therefore examined the intracellular Ca++ signals stimulated by histamine and nicotine, alone and together. In Ca(++)-deficient medium, nicotine-stimulated signals were abolished, whereas histamine-stimulated signals were maintained, demonstrating that nicotine depended entirely on Ca++ influx for its effects. Indeed, the nicotine-stimulated signal could also be prevented using a Ca++ channel blocker, nicardipine. Further, the observation that exposure of BACC to thapsigargin reduced histamine-stimulated Ca++ signals verified that histamine mobilizes Ca++ from intracellular stores. Thus, the two secretogogues mobilize Ca++ from distinct pools. When BACC were stimulated with the two secretogogues together, the resulting Ca++ signal was greater than that from either alone. These data are consistent with a model in which two distinct sources of Ca++ can summate within the cell, producing a greater Ca++ signal and, hence, a greater effect on neurotransmitter release.

  • Isolation and characterization of a regulated form of actin depolymerizing factor.

    23 July 2018

    Actin depolymerizing factor (ADF) is an 18.5-kD protein with pH-dependent reciprocal F-actin binding and severing/depolymerizing activities. We previously showed developing muscle down-regulates ADF (J. R. Bamburg and D. Bray. 1987. J. Cell Biol. 105: 2817-2825). To further study this process, we examined ADF expression in chick myocytes cultured in vitro. Surprisingly, ADF immunoreactivity increases during the first 7-10 d in culture. This increase is due to the presence of a new ADF species with higher relative molecular weight which reacts identically to brain ADF with antisera raised against either brain ADF or recombinant ADF. We have purified both ADF isoforms from myocytes and have shown by peptide mapping and partial sequence analysis that the new isoform is structurally related to ADF. Immunoprecipitation of both isoforms from extracts of cells prelabeled with [32P]orthophosphate showed that the new isoform is radiolabeled, predominantly on a serine residue, and hence is called pADF. pADF can be converted into a form which comigrates with ADF on 1-D and 2-D gels by treatment with alkaline phosphatase. pADF has been quantified in a number of cells and tissues where it is present from approximately 18% to 150% of the amount of unphosphorylated ADF. pADF, unlike ADF, does not bind to G-actin, or affect the rate or extent of actin assembly. Four ubiquitous protein kinases failed to phosphorylate ADF in vitro suggesting that ADF phosphorylation in vivo is catalyzed by a more specific kinase. We conclude that the ability to regulate ADF activity is important to muscle development since myocytes have both pre- and posttranslational mechanisms for regulating ADF activity. The latter mechanism is apparently a general one for cell regulation of ADF activity.

  • Cyclic AMP-dependent protein kinase decreases gamma-aminobutyric acidA receptor-mediated 36Cl- uptake by brain microsacs.

    23 July 2018

    The effect of cyclic AMP (cAMP)-dependent protein phosphorylation on gamma-aminobutyric acidA (GABAA) receptor function was examined using isolated brain membrane vesicles (microsacs). Muscimol-stimulated 36Cl- uptake was studied in mouse brain microsacs permeabilized to introduce the catalytic subunit of cAMP-dependent protein kinase (PKA). At both submaximal and maximally effective concentrations of muscimol, PKA inhibited muscimol-stimulated 36Cl- uptake by approximately 25%. In parallel experiments, PKA and [gamma-32P]ATP were introduced into the microsacs, and we attempted to immunoprecipitate the entire GABAA receptor complex, under nondenaturing conditions, using an anti-alpha 1-subunit antibody. Data from such experiments show that PKA increases the phosphorylation of several microsac proteins, including a 66-kDa polypeptide specifically immunoprecipitated with the GABAA receptor anti-alpha 1 subunit antibody. Phosphopeptide mapping of the 66-kDa polypeptide demonstrated a 14-kDa fragment similar to that obtained with the purified, PKA-phosphorylated GABAA receptor. These results provide evidence that the catalytic subunit of PKA inhibits the function of brain GABAA receptors and demonstrate that this functional change is concomitant with an increase in protein phosphorylation.

  • Trifluoperazine inhibits hippocampal long-term potentiation and the phosphorylation of a 40,000 dalton protein.

    23 July 2018

    Brief high frequency stimulation induces long-term potentiation (LTP) and changes in the endogenous phosphorylation of a 40,000 dalton protein in the hippocampus in a calcium-dependent manner. In the present paper we report that 40 microM trifluoperazine (TFP), a phenothiazine that binds calmodulin and blocks its activity, inhibits LTP in the hippocampal slice. In addition, calmodulin stimulates and TFP inhibits the phosphorylation of the 40,000 dalton protein (as well as that of several other proteins) in a dose-dependent fashion.

  • Enhancement of recombinant alpha 1 beta 1 gamma 2L gamma-aminobutyric acidA receptor whole-cell currents by protein kinase C is mediated through phosphorylation of both beta 1 and gamma 2L subunits.

    23 July 2018

    The gamma-aminobutyric acidA (GABA)A receptor (GABAR) beta 1 and gamma 2L subtypes have been shown to be phosphorylated in vitro by protein kinase C (PKC) [J. Biol. Chem. 267:14470-14476 (1992); Neuron 12:1081-1095 (1994)]. To determine the physiological consequences of phosphorylation of GABAR isoforms containing the beta 1 and gamma 2L subtypes, the specific serine residues phosphorylated by PKC (beta 1 S409, gamma 2L S327 and S343) were changed to alanines through site-directed mutagenesis. Wild-type (alpha 1 beta 1 gamma 2L GABARs) and three mutant GABAR isoforms [alpha 1 beta 1 gamma 2L(S327A, S343A), alpha 1 beta 1(S409A) gamma 2L, and alpha 1 beta 1(S409A) gamma 2L(S327A, S343A) GABARs) were expressed in mouse L929 fibroblasts through transient cotransfection. Recordings were obtained from each cell with the use of the whole-cell patch-clamp technique. The initial recording was made with the use of control intrapipette solution, and a second recording from the same cell was obtained with pipettes containing either constitutively active PKC [protein kinase M (PKM)] or control solution to obtain paired GABA concentration-response relationships. All GABAR isoforms studied had equivalent maximal GABA currents and similar GABA concentration-response profiles under the control condition. Intracellular PKM treatment increased the maximal current and EC50 value in cells expressing wild-type GABARs. However, PKM reimpalement did not significantly change these parameters in cells expressing any of the mutant GABAR isoforms, indicating that the mutation of either the beta 1 or gamma 2L subtype alone was sufficient to prevent enhancement of GABAR current by PKM. No significant changes were obtained during control reimpalement recordings of wild-type or mutant receptors. Furthermore, PKM treatment did not after the time constants of GABA current desensitization kinetics measured from cells expressing wild-type or mutant receptors. These data thus suggest that PKC phosphorylation of the beta 1 and gamma 2L subtypes enhances GABAR current and that both subtypes are required for complete PKC-mediated enhancement of alpha 1 beta 1 gamma 2L GABAR current.

  • Phosphorylation of cytochrome P4502E1 (CYP2E1) by calmodulin dependent protein kinase, protein kinase C and cAMP dependent protein kinase.

    23 July 2018

    Phosphorylation of pure cytochrome P4502E1 (CYP2E1) was achieved in vitro using Ca2+/calmodulin-dependent protein kinase II (CaM kinase II), protein kinase C (PKC) and cAMP-dependent protein kinase (PKA). The stoichiometry and time-course of phosphorylation were determined. CaM kinase II was the most efficient enzyme capable of catalyzing this phosphorylation reaction: the maximum incorporation of 32PO4 was 0.8 mol/mol CYP2E1 in 20 min. PKA phosphorylated a maximum of 0.7 mol of 32PO4/mol of cytochrome within 60 min. The phosphorylation by PKC reached a maximum of 0.19 mol of 32PO4/mol of cytochrome and this occurred within a few minutes of incubation. Limited digestion by S. aureus V8 protease (SAP) of CYP2E1, which had been phosphorylated by either PKA and PKC, yielded a single major phosphopeptide with an M(r) of approximately 18,000. Limited digestion of CYP2E1, that had been phosphorylated by CaM kinase II, yielded phosphorylated polypeptides with M(r) of approximately 18,000 and 15,000. These results raise the possibility that these three kinases may be involved in the regulation of CYP2E1.

  • Imbalance of ADHD diagnosis in the US

    23 November 2015

    Higher numbers of diagnosis exist in some affluent populations, while in poor white populations and ethnic minorities there is under-diagnosis, says Professor Ilina Singh

  • It's August! Will Self demolishes psychiatry after intense introspection & finds kind words for Tom Burns

    5 August 2013

    "Early in Our Necessary Shadow, his lucid, humane and in many ways well-balanced account of the nature and meaning of psychiatry, Tom Burns, professor of social psychiatry at Oxford University, makes a supremely telling remark: "I am convinced psychiatry is a major force for good or I would not have spent my whole adult life in it." This is a form of the logical fallacy post hoc ergo propter hoc ("After this, therefore because of this"), and it seems strange that an academic of such standing should so blithely retail it because, of course, if we reverse the statement it makes just as much sense: "Having spent my whole adult life as a psychiatrist I must maintain the conviction that it is a major force for good.""

  • Study finds virtual reality can help treat severe paranoia

    5 May 2016

    Virtual reality can help treat severe paranoia by allowing people to face situations that they fear, an Oxford University study has found. The virtual reality simulations allowed the patients to learn that the situations they feared (such as a crowded tube train) were actually safe.

  • Can psychological therapies help people who self-harm?

    16 May 2016

    A review by the respected Cochrane organisation, and led by Oxford University Professor of Psychiatry Keith Hawton, has found that psychological therapies, more commonly known as 'talking treatments', may help people who self-harm.

  • Success for Cognitive Research Facility as funding renewed

    29 November 2016

    The NIHR Oxford cognitive health Clinical Research Facility has been awarded £3.7m to continue its life-changing work translating innovative research into better treatments for cognitive health.

  • Antipsychotic medication linked to reduced rate of violent crime

    8 May 2014

    In a new study, Dr Seena Fazel, a consultant forensic psychiatrist at Oxford University, found that people who use antipsychotic medicines to treat psychiatric illness were nearly half as likely to commit a violent crime compared with when they are not using it. Only a minority of patients perpetrate crimes, said Dr. Fazel. "But even in this minority, it may be to a large extent a modifiable risk."

  • Elizabeth Braithwaite shortlisted for Medical Research Council’s Max Perutz Science Writing Award

    3 October 2013

    "Oxford University researcher Elizabeth Braithwaite, from the Department of Psychiatry at Warneford Hospital, was among 11 finalists from 200 applicants in the Medical Research Council’s Max Perutz Science Writing Award. She was shortlisted for her article about research she is undertaking into depression during pregnancy" [Oxford Mail, 03/10/2013, p.8]

  • Applications Invited for Wellcome Trust Oxford DPhil Scheme for Psychiatrists

    21 September 2015

    Psychiatrists at any stage in their training in the UK who wish to do a DPhil (PhD) can apply for this prestigious scheme which pays an appropriate clinical salary, fees, and research costs, for three years. Up to four places are available.

  • BBC World Service: Why does funk music make us want to dance?

    14 March 2016

    Professor Morten Kringelbach, from the University of Oxford Department of Psychiatry, explains how we get pleasure from certain kinds of syncopated beats.

  • Congratulations Marco Narajos, Sophie Behrman & Jane Walker !

    24 July 2015

    Marco Narajos, Sophie Behrman & Jane Walker were shortlisted by the Royal College of Psychiatrists for the 'medical student', 'senior trainee' & ‘academic researcher of the year’ award 2015, respectively.

  • Our research

    1 November 2012

  • Publications

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  • Example Projects

    17 September 2018

  • Files

    30 June 2017

  • Research in Autism

    15 April 2013

    Many groups throughout the University of Oxford and the Oxford area.

  • Service Providers for Autism

    15 April 2013

    description of clinical column

  • News and meetings

    15 April 2013

    Short descripton

  • Research Projects

    30 June 2017

    NIHR Programme Grant- A collaborative programme of research to support the National Suicide Prevention Strategy [+ Additional page attached as Word doc] Multicentre Study of Self-harm in England- A national collaboration to provide a basis for studies of self-harm in England [+ Additional page attached as Word doc Multicentre_for_dept_website.docx] Wellcome Trust Safer Storage of Pesticides Project

  • Subgroups

    26 September 2014

    We have a number of subgroups within the larger Child and Adolescent Group.

  • Taking part

    30 June 2017

    Information for students, clinicians and volunteers