Regulation of protein kinase Mζ synthesis by multiple kinases in long-term potentiation

The persistent activity of protein kinase M zeta (PKM zeta) maintains synaptic long-term potentiation (LTP) and spatial memory, but the interactions between PKM zeta and the other protein kinases implicated in synaptic plasticity are unknown. During LTP, PKM zeta is rapidly synthesized from a PKM zeta mRNA that encodes a protein kinase C zeta(PKC zeta) catalytic domain without a regulatory domain; thus, second messengers that activate full-length PKC isoforms are not required to stimulate PKM zeta. Like other PKCs, however, PKM zeta must be phosphorylated on its activation loop by phosphoinositide-dependent protein kinase-1 (PDK1) for optimal catalytic activity. Thus, two sequential steps are required for the persistent increased PKM zeta activity that maintains LTP: de novo synthesis of PKM zeta and phosphorylation of its activation loop. Here, using a panel of antisera to phosphorylated and nonphosphorylated sites on PKM zeta, we show that PI3-kinase (phosphoinositide 3-kinase), CaMKII (Ca2+/calmodulin-dependent protein kinase II), MAPK (mitogen-activated protein kinase), PKA (protein kinase A), mTOR (mammalian target of rapamycin), all important for LTP induction, as well as preexisting PKM zeta, regulate the new synthesis of PKM zeta during LTP. In contrast, PDK1 forms a complex with PKM zeta and maintains maximal phosphorylation of its activation loop. Thus, the two steps of PKM zeta formation serve separate functions in LTP: the initial regulated synthesis of PKM zeta is the site of convergence and integration for multiple kinases of induction, whereas the constitutive phosphorylation of PKM zeta by PDK1 initiates the persistent autonomous activity that sustains maintenance.