Conventional protein kinase C isoforms mediate neuroprotection induced by phorbol ester and estrogen.
Rapid signal transduction pathways play a prominent role in mediating neuroprotective actions of estrogen in the CNS. We have previously shown that estrogen-induced neuroprotection of primary cerebrocortical neurons from beta-amyloid peptide (Abeta) toxicity depends on activation of protein kinase C (PKC). PKC activation with phorbol-12-myristate-13-acetate (PMA) also provides neuroprotection in this paradigm. Because the PKC family includes several isoforms that have opposing roles in regulating cell survival, we sought to identify which PKC isoforms contribute to neuroprotection induced by PMA and estrogen. We detected protein expression of multiple PKC isoforms in primary neuron cultures, including conventional (alpha, betaI, betaII), novel (delta, epsilon, theta) and atypical (zeta, iota/lambda) PKC. Using a panel of isoform-specific peptide inhibitors and activators, we find that novel and atypical PKC isoforms do not participate in the mechanism of either PMA or estrogen neuroprotection. In contrast, a selective peptide activator of conventional PKC isoforms provides dose-dependent neuroprotection against Abeta toxicity. In addition, peptide inhibitors of conventional, betaI, or betaII PKC isoforms significantly reduce protection afforded by PMA or 17beta-estradiol. Taken together, these data provide evidence that conventional PKC isoforms mediate phorbol ester and estrogen neuroprotection of cultured neurons challenged by Abeta toxicity.
Cordey
Myriam
M
Neuroscience Graduate Program and Andrus Gerontology Center, University of Southern California, Los Angeles, California 90089-0191, USA.
Pike
Christian J
CJ
D016229:Amyloid beta-Peptides / Q000633:toxicity; D000818:Animals; D015153:Blotting, Western; D002458:Cell Fractionation; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D020536:Enzyme Activators / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology*; D007527:Isoenzymes / Q000378:metabolism; D018696:Neuroprotective Agents; D010703:Phorbol Esters / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D020536:Enzyme Activators; D004967:Estrogens; D007527:Isoenzymes; D018696:Neuroprotective Agents; D010703:Phorbol Esters; D004958:Estradiol; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate