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SfN Atlanta: Working Both Sides of the Synapse in Mood Disorders

Editor's Note: In the second of her meeting missives from the Neurosciences 2006 meeting in Atlanta, Susannah F. Locke of the University of Pennsylvania reports on a symposium entitled, “Protein Trafficking at Synapses and Therapeutic Agents for Mood Disorders.” Co-chaired by Maurizio Popoli of the University of Milan and Mark Rasenick of the University of Illinois, the session covered the regulation of both presynaptic and postsynaptic trafficking in the context of pharmacotherapy for mood disorders.


Regulation of NET by CamKII and by ubiquitination
14 November 2006. Uhna Sung, of Vanderbilt University, gave a presentation entitled “Protein Complexes to Support Trafficking of Antidepressant-sensitive Norepinephrine Transporters.” She discussed the regulation of norepinephrine transporters (NETs) by calcium/calmodulin-dependent protein kinases I and II (CaMKI and -II) and by ubiquitination. CaMKI and -II and E3 ubiquitin ligase Nedd4 were identified from a NET-associated proteome study using CAD (a noradrenergic neuroblastoma line) cells exogenously expressing NET. Sung had previously used the NET proteome to demonstrate associations with both protein phosphatase 2A and 14-3-3 (Sung et al., 2005).

Sung presented data implicating both CaMKI and -II in calcium-dependent NET trafficking. CaMKI and -II siRNA expression in CAD-NET cells attenuated calcium-dependent NET trafficking. CaMKII siRNA expression in CAD-NET cells also decreased NET on the cell surface. Depletion of calcium produced a similar effect which was dependent on an amino-terminus domain of NET. Although Sung did not include this evidence in her talk, she and her collaborators have shown that amphetamine reduces NET localization on the cell surface in a CaMKII-dependent manner (Dipace et al., 2006).

Sung also identified many ubiquitin system enzymes in the NET proteome, including E3 ubiquitin ligase Nedd4. Ubiquitination is a cellular process for tagging proteins for degradation. Immunoprecipitation of NET from CAD cells revealed interactions of NET with Nedd4, and immunofluorescence microscopy demonstrated that Nedd4 and NET colocalize in neuronal processes of cultured primary sympathetic neurons. Treatment with the antidepressant desipramine (a norepinephrine reuptake inhibitor) decreased the ubiquitination of NET and increased total protein levels of NET.

AMPA trafficking in vivo
Jing Du’s talk, “Modulation of AMPA Receptor Trafficking by Mood Stabilizers: Involvement in Antimanic Effects in Animal Models,” focused on administration of a TAT-tagged peptide to modify AMPA trafficking in vivo. Du, of the National Institute of Mental Health, has previously published work exploring the regulation of AMPA glutamate receptor subunit 1 (GluR1) by anti-manic drugs (Du et al., 2004). In this paper he demonstrated that chronic lithium or valproate treatment in rats decreased GluR1 at the synapse and decreased GluR1 phosphorylation at its PKA site. In vitro, these effects could be reversed by treatment with the PKA activator Sp-cAMP.

Du presented new in vivo data demonstrating that a TAT-tagged peptide had effects similar to lithium and valproate in mice. The peptide included the PKA phosphorylation motif of GluR1 and a TAT tag (to ensure delivery across the blood-brain barrier). After several days of peptide injections, mice displayed a decrease in synaptic GluR1 and GluR2. Du also shared preliminary research suggesting that the peptide interferes with amphetamine-induced behavior. Peptide treatment seemed to impact two animal models of manic behavior, decreasing amphetamine-induced hyperactivity and reducing amphetamine association in conditioned place preference tests.

Antidepressants and glutamate release
Maurizio Popoli, of the University of Milan, gave a presentation entitled “Presynaptic Protein Interactions Regulating Glutamate Release in the Action of Stress and Antidepressants.” The majority of his talk covered previously published work on antidepressants (Bonanno et al., 2005).

Popoli described his studies using synaptosomes (purified synaptic terminals) prepared from rats chronically treated with antidepressants. Rats that were administered fluoxetine, reboxetine, or desipramine had similar changes in glutamate release, even though these antidepressants work through different mechanisms. Synaptosomes from antidepressant-treated rats displayed a decrease in depolarization-evoked, but not ionomycin-evoked, glutamate release. GABA release was not affected, suggesting a shift in excitatory versus inhibitory neurotransmission.

Popoli then discussed other studies in which synaptosomes were purified further into a synaptic membrane fraction (which contained the readily releasable pool of vesicles) and a total synaptic vesicle fraction. Synaptic membranes from rats treated with fluoxetine or reboxetine had lower expression of the SNARE proteins syntaxin, SNAP-25, and synaptobrevin. In addition, syntaxin I availability for the SNARE complex was likely inhibited due to changes in protein-protein interactions. Synaptic membranes from treated rats showed less interaction between syntaxin I and alpha-CaM kinase II, but more interaction between syntaxin I and Munc-18. Alpha-CaM kinase II is thought to increase, whereas Munc-18 is thought to decrease syntaxin I’s assembly into the SNARE complex. More recent research in the Popoli lab includes explorations of glutamate release modulation in animal models of depression and stress.

Depression and G protein signaling
Robert Donati, of the Illinois College of Optometry, gave a talk entitled “G Protein Signaling in Microdomains of the Plasma Membrane Is Altered in Depression or by Antidepressant Treatment.” Various types of antidepressant therapy, including electroconvulsive shock therapy and a wide range of antidepressant drugs, increase coupling between Gs-alpha and adenylyl cyclase.

Donati studied the membrane localization of Gs-alpha in Triton X-100 soluble and Triton X-100 insoluble fractions, the latter of which includes both lipid rafts and caveolae. Localization in lipid rafts/caveolae essentially inhibits Gs-alpha by separating it from G-protein coupled receptors and by enhancing its internalization. Donati explained that B-adrenergic signaling in C6 glioma cells causes Gs-alpha to internalize. This internalization is lost when the lipid rafts/caveolae are chemically disrupted (Allen et al., 2005).

Donati presented data exploring the effects of antidepressants on Gs-alpha localization (Donati and Rasenick, 2005). In C6 glioma cells, chronic desipramine or fluoxetine treatment shifted a large percentage of Gs-alpha from the lipid rafts/caveolae fraction to the Triton X-100 soluble fraction. Microtubule disruption created the same pattern of localization, which suggests that microtubules help anchor Gs-alpha in lipid rafts/caveolae.

Donati also shared newer work on human patients. Postmortem studies on depressed patients that had committed suicide showed that there was more Gs-alpha associated with lipid rafts/caveolae in cortex and in cerebellum than in controls.—Susannah F. Locke.

 
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