Focus on Protein kinase A and protein kinase C, critical components of signal transduction system, in mood disorders and suicide 1
Depression is among the most prevalent forms of mental disorders, affecting 10–15% of the US population, with high rates of comorbidity and frequent suicidal behaviour. Tragically, about 30000 lives are lost each year by suicide (Minino and Smith, 2001). Despite significant progress in research, the pathophysiology of depression and suicide is poorly understood. A number of studies suggest that abnormalities in signalling mechanisms may be crucial to various psychiatric disorders, including depression and suicide (Dwivedi et al., 2002, 2003; Jope et al., 1998; Pacheco et al., 1996; Pandey et al., 2002a). Particular attention has been paid to examining protein phosphorylation and dephosphorylation and the activation and repression of transcription factors, which are key processes in signalling mechanisms, and ultimately in modulating the expression of genes involved in various neuronal functions. Two important protein phosphorylating enzymes, protein kinase A (PKA) and protein kinase C (PKC), are components of the adenylyl cyclase-cyclic AMP (AC-cAMP) and the phosphoinositide (PI) signalling systems respectively. Activation of PKC by diacylglycerol is associated with the translocation of the enzyme from the cytoplasm to the membrane and then causes phosphorylation of important proteins and transcription factors such as cAMP response element-binding (CREB) protein, which regulates the expression of genes containing CRE consensus in their promoters. As is the case with PKC, the activation of PKA by cAMP also phosphorylates a diverse number of target proteins in both cytoplasm and the nuclear compartment. One such target in the nucleus is CREB.(Received August 25 2004)
(Reviewed August 29 2004)
(Accepted August 29 2004)
c1 Dr G. N. Pandey, The Psychiatric Institute, Department of Psychiatry, University of Illinois at Chicago, 1601 W. Taylor Street, Chicago, IL 60612, USA. Tel.: (312) 413-4540 Fax: (312) 413-4547 E-mail: [email protected]
1 See Akin et al. (this issue). Signal transduction abnormalities in melancholic depression.