Activation of protein kinase A and atypical protein kinase C by A(2A) adenosine receptors antagonizes apoptosis due to serum deprivation in PC12 cells

We found in the present study that stimulation of A(2A) adenosine receptors (A(2A)-R) prevents apoptosis in PC12 cells. This A(2A)-protective effect w as blocked by protein kinase A (PKA) inhibitors and was not observed in a P KA deficient PC12 variant. Stimulation of PKA also prevented apoptosis, sug gesting that PKA is required for the protective effect of A(2A)-R. A genera l PKC inhibitor, but not down-regulation of conventional and novel PKCs, re adily blocked the protective effect of A(2A)-R stimulation and PKA activati on, suggesting that atypical PKCs (aPKCs) serve a critical role downstream of PKA Consistent with this hypothesis, stimulation of A(2A)-R or PRA enhan ced nuclear aPKC activity. In addition, the A(2A)-protective effect was blo cked by a specific inhibitor of one aPKC, PKC zeta, whereas overexpression of a dominant-positive PKC zeta enhanced survival. In contrast, inhibitors of MAP kinase and phosphatidylinositol 3-kinase did not modulate the A(2A)- protective effect. Dominant-negative Akt also did not alter the A(2A)-prote ctive effect, whereas it significantly reduced the protective action of ner ve growth factor. Collectively, these data suggest that aPKCs can function downstream of PKA to mediate the A(2A)-R-promoted survival of PC12 cells. F urthermore, the results indicate that different extracellular stimuli can e mploy distinct signaling pathways to protect against apoptosis induced by t he same insult.