Regulation of Protein Kinase Mζ Synthesis by Multiple Kinases in Long-Term Potentiation

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Abstract
The persistent activity of protein kinase Mζ (PKMζ) maintains synaptic long-term potentiation (LTP) and spatial memory, but the interactions between PKMζ and the other protein kinases implicated in synaptic plasticity are unknown. During LTP, PKMζ is rapidly synthesized from a PKMζ mRNA that encodes a protein kinase Cζ (PKCζ) catalytic domain without a regulatory domain; thus, second messengers that activate full-length PKC isoforms are not required to stimulate PKMζ. Like other PKCs, however, PKMζ 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 PKMζ activity that maintains LTP: de novo synthesis of PKMζ and phosphorylation of its activation loop. Here, using a panel of antisera to phosphorylated and nonphosphorylated sites on PKMζ, 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 PKMζ, regulate the new synthesis of PKMζ during LTP. In contrast, PDK1 forms a complex with PKMζ and maintains maximal phosphorylation of its activation loop. Thus, the two steps of PKMζ formation serve separate functions in LTP: the initial regulated synthesis of PKMζ is the site of convergence and integration for multiple kinases of induction, whereas the constitutive phosphorylation of PKMζ by PDK1 initiates the persistent autonomous activity that sustains maintenance.