Role of protein kinase Calpha in the regulated secretion of the amyloid precursor protein.
Protein kinase C (PKC) has a key role in the signal transduction machinery involved in the regulation of amyloid precursor protein (APP) metabolism. Direct and indirect receptor-mediated activation of PKC has been shown to increase the release of soluble APP (sAPPalpha) and reduce the secretion of beta-amyloid peptides. Experimental evidence suggests that specific isoforms of PKC, such as PKCalpha and PKC epsilon, are involved in the regulation of APP metabolism. In this study, we characterized the role of PKCalpha in the regulated secretion of APP using wild-type SH-SY5Y neuroblastoma cells and cells transfected with a plasmid expressing PKCalpha antisense cDNA. Cells expressing antisense PKCalpha secrete less sAPPalpha in response to phorbol esters. In contrast, carbachol increases the secretion of sAPPalpha to similar levels in wild-type cells and in cells transfected with antisense PKCalpha by acting on APP metabolism through an indirect pathway partially involving the activation of PKC. These results suggest that the direct PKC-dependent activation of the APP secretory pathway is compromised by reduced PKCalpha expression and a specific role of this isoform in these mechanisms. On the other hand, indirect pathways that are also partially dependent on the mitogen-activated protein kinase signal transduction mechanism remain unaffected and constitute a redundant, compensatory mechanism within the APP secretory pathway.
Racchi
M
M
Department of Experimental and Applied Pharmacology, University of Pavia, Viale Taramelli 14, Pavia 27100, Italy.
Mazzucchelli
M
M
Pascale
A
A
Sironi
M
M
Govoni
S
S
D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D002217:Carbachol / Q000494:pharmacology; D002273:Carcinogens / Q000494:pharmacology; D018678:Cholinergic Agents / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D009447:Neuroblastoma; D009474:Neurons / Q000201:enzymology* / Q000378:metabolism*; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D051571:Protein Kinase C-alpha; D011950:Receptors, Cholinergic / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured
D016564:Amyloid beta-Protein Precursor; D002273:Carcinogens; D018678:Cholinergic Agents; D007527:Isoenzymes; D011950:Receptors, Cholinergic; D002217:Carbachol; C496628:PRKCA protein, human; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D013755:Tetradecanoylphorbol Acetate