MINI–REVIEW Nociceptive and behavioural sensitisation by protein kinase Ce signalling in the CNS

Protein kinase C (PKC) (EC 2.7.11.13) (Enzyme Nomenclature 1992), represents a family of phospholipid-dependent serine/threonine phosphotransferases which are members of the protein kinase A (PKA), G and C superfamily. Most isoforms of PKC are activated in the presence of calcium (Ca) and diacylglycerol (DAG) (Nishizuka 1995). Once activated, these isozymes play central regulatory roles in a multitude of cellular processes, including proliferation, differentiation, tumourigenesis, cytoskeletal remodelling and modulation of ion channels/receptors (Battaini 2001). Extensive investigations of activation mechanisms in combination with rational drug design contributed to the development of isoform-specific modulators with therapeutic potential (Irie et al. 2005). During the past decade, alterations in PKC signalling in the pathophysiology of psychiatric disorders have been observed. Moreover, a number of mood stabilisers seem to affect PKC activity and expression. It has been proposed that lithium and valproate mediate mood stabilising effects by altering PKC signalling (Manji and Lenox 1999). Acute treatment of rats with the antipsychotic drug haloperidol increases membrane localisation PKC in hippocampus, striatum and cortex (Dwivedi and Pandey 1999). Downstream of PKC, a decreased phosphorylation of myristoylated alanine-rich C kinase substrate has been observed in the prefrontal cortex and hippocampus of suicide subjects (Pandey et al. 2003). From these observations, it has become evident that PKC isoforms are differentially