Major depression (MDD) is a common and serious disorder, but the biological basis remains elusive. Signal transduction mechanisms, including critical enzymes such as protein kinases A (PKA) and C (PKC), appear to be altered in MDD, particularly in the melancholic (MEL) subtype. Our preliminary data show: (1) A parallel reduction in the activity of both PKA and PKC in MDD, MEL subtype (but not in the non-melancholies [non- MEL]) relative to controls; (2) A concomitant decrease in [3H]cyclic AMP binding to PKA and [3H]PDBU binding to PKC; (3) Reduced levels of specific kinase protein isoforms. As well, we have recently demonstrated an apparent uncoupling of the PKC-linked serotonin 2A (5-HT2A) receptors from Gq proteins in this population. This project will evaluate potential causes and consequences of the findings. We have used a cultured human fibroblast (FB) model, but now can extend the investigation to post-mortem brain tissue (PMB) from well- characterized depressed suicide victims and normal controls (for which we also have preliminary data). We propose to compare in PMB from persons identified as MEL, non-MEL, and controls: (1) The level of CREB phosphorylation after PKA and PKC activation; (2) The binding of [3H] cyclic AMP to PKA and [3H]phorbol dibutyrate to PKC; and test (3) The possibility of a concomitant reduction of binding and activity of kinases. We also will contrast the following in the three study groups: (4) Protein and mRNA levels of PKA and PKC protein isoforms in PMB and FB; (5) Rates of degradation of PKA and PKC isoforms by pulse-chase immuno- precipitation in FB; (6) The comparative effects of key regulators of kinase activity by the inhibition of phosphodiesterase IV and protein phosphatase 2A and evaluating their mRNA and protein expression. We also will examine the apparent uncoupling of 5-HT2A receptors in MEL by contrasting between groups: (7) PI hydrolysis after a specific 5-HT2A agonist and alternative Gq-coupled receptor agonists in FB and PMB; (8) GTPyS incorporation following activation of 5-HT2A receptors in PMB; (9) Differential agonist and antagonist binding in PMB; (10) CREB-P formation after activation with a 5-HT2A agonist and alternative Gq-coupled receptor agonist in FB and PMB. These studies may shed light on important cellular mediators of depression and provide new targets for amelioration. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH073630-03
Application #
7347606
Study Section
Neural Basis of Psychopathology, Addictions and Sleep Disorders Study Section (NPAS)
Program Officer
Meinecke, Douglas L
Project Start
2006-02-01
Project End
2010-01-31
Budget Start
2008-02-01
Budget End
2010-01-31
Support Year
3
Fiscal Year
2008
Total Cost
$301,824
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Psychiatry
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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Kálmán, Sára; Garbett, Krassimira A; Vereczkei, Andrea et al. (2014) Metabolic stress-induced microRNA and mRNA expression profiles of human fibroblasts. Exp Cell Res 320:343-53
Gibson, Sara A; Korade, Željka; Shelton, Richard C (2012) Oxidative stress and glutathione response in tissue cultures from persons with major depression. J Psychiatr Res 46:1326-32
Shelton, R C; Claiborne, J; Sidoryk-Wegrzynowicz, M et al. (2011) Altered expression of genes involved in inflammation and apoptosis in frontal cortex in major depression. Mol Psychiatry 16:751-62
Shelton, Richard C; Miller, Andrew H (2010) Eating ourselves to death (and despair): the contribution of adiposity and inflammation to depression. Prog Neurobiol 91:275-99
Shelton, Richard C; Hal Manier, D; Lewis, David A (2009) Protein kinases A and C in post-mortem prefrontal cortex from persons with major depression and normal controls. Int J Neuropsychopharmacol 12:1223-32
Matrisciano, Francesco; Bonaccorso, Stefania; Ricciardi, Angelo et al. (2009) Changes in BDNF serum levels in patients with major depression disorder (MDD) after 6 months treatment with sertraline, escitalopram, or venlafaxine. J Psychiatr Res 43:247-54
Shelton, R C; Sanders-Bush, E; Manier, D H et al. (2009) Elevated 5-HT 2A receptors in postmortem prefrontal cortex in major depression is associated with reduced activity of protein kinase A. Neuroscience 158:1406-15

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