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

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 signifi cance of the fi ndings 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-specifi c therapeutic interventions for these disorders.

cAMP-mediated secretion of brain-derived neurotrophic factor in developing airway smooth muscle

“…However, in ASM, regulation of BDNF expression and secretion are not well defined. Among the several factors that may regulate BDNF at least in other cell types such as neurons, two pathways particularly important to airway physiology are the cyclic nucleotides cGMP [33–35] and cAMP [36–39]. Previous studies in neurons [40–42] and endothelium [43, 44] consistently show that cAMP regulates increases in BDNF secretion.…”

Norepinephrine Induces BDNF and Activates CREB and Discriminates among Protein Kinase C Isoforms in Cultured Embryonic Hippocampal Neurons

“…However, this could also indicate that PKA [56] Norepinephrine significantly reversed the suppressing effects of GF, being significantly higher than that of GF alone (p < 0.001). Veh, vehicle control; NE, norepinephrine (100 nM); GF, bisindoylmaleimide (5 μM); *Significantly different from vehicle controls.…”

Human dermal fibroblasts in psychiatry research

“…This PKA/PKC-deficit of CREB activation in MD deserves more attention, considering that CREB plays an essential role in activity-driven functional and structural neural changes (Benito and Barco, 2015) and that monoamines, stress hormones and antidepressants affect the CREB/BDNF pro-survival pathway (for a comprehensive review see Dwivedi et al, 2008). Notably, some CREB-mediated cellular functions are neuron-specific, but others – like the circadian rhythm regulation – are also present in peripheral cells (Druzd et al, 2014; Gaspar et al, 2014; McCarthy et al, 2013a).…”