Protein kinase C signal transduction regulation in Physiological and pathological aging

Calcium/Phospholipid-regulated Protein kinase C (PKC) signalling is known to be involved in cellular functions relevant in brain health and disease, including ion channel modulation, receptor regulation, neurotransmitter release, synaptic plasticity and survival (1). Brain aging is characterized by altered neuronal molecular cascades and interneuronal communication in response to various stimuli. Over the last years we have provided evidence that in rodents, in spite of no changes in PKC isoform levels (both calcium-dependent and calcium-independent), the activation/translocation process of the calciumdependent and –independent kinases and the content of the adaptor protein RACK1 (Receptor for Activated C Kinase-1) are deficitary in physiological brain aging (2). Along this line the age-associated impairment in rodent alveolar macrophage and cardiac responsiveness to stimuli reflect a deficit in both PKC activation and expression of RACK1, underscoring the importance and the extension of these observations to non neuronal tissues as well. Moreover human studies have shown that PKC and its adaptor protein RACK1 are interdependent: in pathological brain aging (i.e. Alzheimer’s Disease) calcium-dependent PKC translocation and RACK1 levels are deficitary in an area-selective manner (3); similarly others have shown that conditions associated with PKC overactivation (i.e. bipolar disorder) are coupled with increased expression and association of RACK1 with PKC (for a review see 4). These data point to the notion that, in addition to a lipid environment alteration, changes in protein-protein interactions may impair the mechanisms of PKC activation in aging. It is interesting to note that interventions directed to counteract the age-related functional loss restore in parallel the PKC activation and adaptor protein machinery expression. Abetter insight of the factors controlling PKC activation may be important not only to elucidate the molecular basis of signal transmission , but also to identify new strategies aimed to correct or even prevent age-dependent alterations in cell to cell communication.