Increased Cyclic AMP‐Dependent Protein Kinase Activity in Postmortem Brain from Patients with Bipolar Affective Disorder

Section of Biochemical Psychiatry, Centre for Addiction and Mental Health-Clarke Division, University of Toronto, Ontario, Canada.
Journal of Neurochemistry (Impact Factor: 4.28). 11/1999; 73(4):1704-10. DOI: 10.1046/j.1471-4159.1999.731704.x
Source: PubMed


Previous observations of reduced [3H]cyclic AMP binding in postmortem brain regions from bipolar affective disorder subjects imply cyclic AMP-dependent protein kinase function may be altered in this illness. To test this hypothesis, basal and stimulated cyclic AMP-dependent protein kinase activity was determined in cytosolic and particulate fractions of postmortem brain from bipolar disorder patients and matched controls. Maximal enzyme activity was significantly higher (104%) in temporal cortex cytosolic fractions from bipolar disorder brain compared with matched controls. In temporal cortex particulate fractions and in the cytosolic and particulate fractions of other brain regions, smaller but statistically nonsignificant increments in maximal enzyme activity were detected. Basal cyclic AMP-dependent protein kinase activity was also significantly higher (40%) in temporal cortex cytosolic fractions of bipolar disorder brain compared with controls. Estimated EC50 values for cyclic AMP activation of this kinase were significantly lower (70 and 58%, respectively) in both cytosolic and particulate fractions of temporal cortex from bipolar disorder subjects compared with controls. These findings suggest that higher cyclic AMP-dependent protein kinase activity in bipolar disorder brain may be associated with a reduction of regulatory subunits of this enzyme, reflecting a possible adaptive response of this transducing enzyme to increased cyclic AMP signaling in this disorder.

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    • "They found significantly decreased [3H]cAMP binding to regulatory subunits in the cytosolic but not in the membrane fractions of frontal, temporal, and occipital cortices, cerebellum, and thalamus of bipolar patients (Rahman et al 1997). They further observed greater basal and cAMP-stimulated PKA activity, and lower EC50 values for cAMP stimulation of PKA activity, in the temporal cortex of bipolar patients (Fields et al 1999). "
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    ABSTRACT: Mood disorders are among the most prevalent and recurrent forms of psychiatric illnesses. In the last decade, there has been increased understanding of the biological basis of mood disorders. In fact, novel mechanistic concepts of the neurobiology of unipolar and bipolar disorders are evolving based on recent pre-clinical and clinical studies, most of which now focus on the role of signal transduction mechanisms in these psychiatric illnesses. Particular investigative emphasis has been given to the role of phosphorylating enzymes, which are crucial in regulating gene expression and neuronal and synaptic plasticity. Among the most important phosphorylating enzyme is protein kinase A (PKA), a component of adenylyl cyclase-cyclic adenosine monophosphate (AC-cAMP) signaling system. In this review, we critically and comprehensively discuss the role of various components of AC-cAMP signaling in mood disorders, with a special focus on PKA, because of the interesting observation that have been made about its involvement in unipolar and bipolar disorders. We also discuss the functional significance of the findings regarding PKA by discussing the role of important PKA substrates, namely, Rap-1, cyclicAMP-response element binding protein, and brain-derived neurotrophic factor. These studies suggest the interesting possibility that PKA and related signaling molecules may serve as important neurobiological factors in mood disorders and may be relevant in target-specific therapeutic interventions for these disorders.
    Neuropsychiatric Disease and Treatment 03/2008; 4(1):161-76. DOI:10.2147/NDT.S2380 · 1.74 Impact Factor
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    • "Most investigators have found decreases in [ 3 H]cAMP binding and in PKA activity and PKA subunits in patients with depression (Manier et al., 1996 ; Perez et al., 2001 ; Shelton et al., 1996) and in post-mortem brain from depressed suicide victims (Dwivedi et al., 2004a). On the other hand, increased catalytic activity of PKA and decreased [ 3 H]cAMP binding have been reported in the post-mortem brain of bipolar patients (Fields et al., 1999 ; Rahman et al., 1997) and increased [ 3 H]cAMP-mediated phosphorylation in platelets of bipolar patients (Perez et al., 1995). Of interest, however , is the change in expression of PKA subunits in these disorders. "
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    • "(Perez et al., 1995, 1999, 2000, 2001; Pandey et al., 1998; Fields et al., 1999; Young et al., 1999; Wang et al., 1999 "
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    ABSTRACT: Phosphorylation of extracellular signal-regulated kinases (ERK 1/2) represents a converging intracellular signalling pathway which is involved in the modulation of gene transcription and may contribute to the feed-back regulation of neurotransmitter receptor functioning. The purpose of the current study was to investigate the serotonin-mediated phosphorylation of ERK 1/2 in platelets from patients (n=17) with panic disorder, with respect to healthy volunteers (n=17). Patients presented a severe symptomatology as assessed by the self-report rating scales for panic-agoraphobic (PAS-SR) and mood (MOOD-SR) spectrum, and by Clinical Global Impression Severity Scale (CGI-S). In platelets from healthy volunteers, serotonin induced a rapid increase of ERK 1/2 phosphorylation with a transient monophasic kinetic. The dose–response curves showed this effect was concentration dependent with an average of the EC50 value of 22.8±2.4 μM. Platelet pre-incubation with 5HT1A and 5HT2A antagonists, pindobind and ritanserin, significantly inhibited serotonin-mediated kinase activation with an EC50 of 3.2±0.2 and 1.99±0.08 nM, respectively, suggesting an involvement of these specific receptor subtypes in serotonin-mediated response. Furthermore, the 5HT1A and 5HT2A agonists, 8-hydroxy-N,N-dipropyl-aminotetralin (8OH-DPAT) and 1-(2,5-dimethoxy)-4-iodophenyl-2-aminopropane (DOI), were able to modulate ERK 1/2 phosphorylation in a concentration-dependent manner with an EC50 value of 3.1±0.2 and 76±4.5 nM, respectively.
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