Adenylyl cyclase-cyclicAMP signaling in mood disorders: Role of the crucial phosphorylating enzyme protein kinase A

Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago Chicago, Illinois 60612, USA.
Neuropsychiatric Disease and Treatment (Impact Factor: 1.74). 03/2008; 4(1):161-76. DOI: 10.2147/NDT.S2380
Source: PubMed


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.

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    • "In PHP 1A, we should expect a Gs protein hypoactivation, reduced intracellular cAMP levels and PKA hypoactivation. However, considering the theories about the hyperactivation of cAMP and PKA signaling in BD [2], the presence of the disorder in the patient might be explained by the alternative activation of PKC signaling. "
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    ABSTRACT: Pseudohypoparathyroidism type 1A and its association with bipolar disorder (BD) have never been reported so far. We report a new case with both clinical entities and discuss the potential pathophysiological mechanisms of this association (protein kinase A hypoactivation, parathyroid hormone, hypocalcemia, protein kinase C activation, vitamin D deficiency). In this patient, the correction of the underlying calcium and vitamin D deficiencies leads to a better BD outcome and lower dosage of psychopharmacological agents. The conclusions might be generalized for a better understanding and management of these conditions. Copyright © 2015. Published by Elsevier Inc.
    General hospital psychiatry 06/2015; 37(5). DOI:10.1016/j.genhosppsych.2015.06.008 · 2.61 Impact Factor
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    • "Finally, to demonstrate the applicability of viral profiling to mental disease, we recruited 10 additional subjects who were age-matched and sex-matched to our initial controls, but suffered from bipolar disorder. Fibroblasts from each subject were infected with reporters for CREB signaling, which has been previously implicated in this disease (Dwivedi & Pandey, 2008). CREB induction in response to forskolin stimulation of adenyl cyclase was then measured in these fibroblasts, both separately and again in the presence of the previous controls. "
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    ABSTRACT: Various lines of evidence suggest a mechanistic role for altered cAMP-CREB (cAMP response element - binding protein) signaling in depressive and affective disorders. However, the establishment and validation of human inter-individual differences in this and other major signaling pathways has proven difficult. Here, we describe a novel lentiviral methodology to investigate signaling variation over long periods of time directly in human primary fibroblasts. On a cellular level, this method showed surprisingly large inter-individual differences in three major signaling pathways in human subjects that nevertheless correlated with cellular measures of genome-wide transcription and drug toxicity. We next validated this method by establishing a likely role for cAMP-mediated signaling in a human neuroendocrine response to light - the light-dependent suppression of the circadian hormone melatonin - that shows wide inter-individual differences of unknown origin in vivo. Finally, we show an overall greater magnitude of cellular CREB signaling in individuals with bipolar disorder, suggesting a possible role for this signaling pathway in susceptibility to mental disease. Overall, our results suggest that genetic differences in major signaling pathways can be reliably detected with sensitive viral-based reporter profiling, and that these differences can be conserved across tissues and be predictive of physiology and disease susceptibility.
    European Journal of Neuroscience 06/2014; 40(1). DOI:10.1111/ejn.12602 · 3.18 Impact Factor
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    • "CREB is one of the most studied phosphorylation-activated transcription factors linked to depression, and its activation plays a critical role in inducing a transcription-dependent program for gene expression such as BDNF [22], [23]. The status of CREB phosphorylation at serine 133 is induced by multiple upstream regulators, including ERK and PKA [22], [27], [28]. Reduced expression and activity in ERK, PKA, and CREB have been seen in depressive suicide victims [37]–[39]. "
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    ABSTRACT: Studies indicate that perinatal opioid exposure produces a variety of short- and long-term neurobehavioral consequences. However, the precise modes of action are incompletely understood. Buprenorphine, a mixed agonist/antagonist at the opioid receptors, is currently being used in clinical trials for managing pregnant opioid addicts. This study provides evidence of depression-like consequence following prenatal exposure to supra-therapeutic dose of buprenorphine and sheds light on potential mechanisms of action in a rat model involving administration of intraperitoneal injection to pregnant Sprague-Dawley rats starting from gestation day 7 and lasting for 14 days. Results showed that pups at postnatal day 21 but not the dams had worse parameters of depression-like neurobehaviors using a forced swimming test and tail suspension test, independent of gender. Neurobehavioral changes were accompanied by elevation of oxidative stress, reduction of plasma levels of brain-derived neurotrophic factor (BDNF) and serotonin, and attenuation of tropomyosin-related kinase receptor type B (TrkB) phosphorylation, extracellular signal-regulated kinase (ERK) phosphorylation, protein kinase A activity, cAMP response element-binding protein (CREB) phosphorylation, and CREB DNA-binding activity. Since BDNF/serotonin and CREB signaling could orchestrate a positive feedback loop, our findings suggest that the induction of oxidative stress, reduction of BDNF and serotonin expression, and attenuation of CREB signaling induced by prenatal exposure to supra-therapeutic dose of buprenorphine provide evidence of potential mechanism for the development of depression-like neurobehavior.
    PLoS ONE 12/2013; 8(12):e82262. DOI:10.1371/journal.pone.0082262 · 3.23 Impact Factor
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