Protein kinase Mζ synthesis from a brain mRNA encoding an independent protein kinase Cζ catalytic domain -: Implications for the molecular mechanism of memory

Protein kinase Mzeta (PKMzeta) is a newly described form of PKC that is necessary and sufficient for the maintenance of hippocampal long term potentiation (LTP) and the persistence of memory in Drosophila. PKMzeta is the independent catalytic domain of the atypical PKCzeta isoform and produces long term effects at synapses because it is persistently active, lacking autoinhibition from the regulatory domain of PKCzeta. PKM has been thought of as a proteolytic fragment of PKC. Here we report that brain PKMzeta is a new PKC isoform, synthesized from a PKMzeta mRNA encoding a PKCzeta catalytic domain without a regulatory domain. Multiple zeta-specific antisera show that PKMzeta is expressed in rat forebrain as the major form of zeta in the near absence of full-length PKCzeta. A PKCzeta knockout mouse, in which the regulatory domain was disrupted and catalytic domain spared, still expresses brain PKMzeta, indicating that this form of PKM is not a PKCzeta proteolytic fragment. Furthermore, the distribution of brain PKMzeta does not correlate with PKCzeta mRNA but instead with an alternate zeta RNA transcript thought incapable of producing protein. In vitro translation of this RNA, however, generates PKMzeta of the same molecular weight as that in brain. Metabolic labeling of hippocampal slices shows increased de novo synthesis of PKMzeta in LTP. Because PKMzeta is a kinase synthesized in an autonomously active form and is necessary and sufficient for maintaining LTP, it serves as an example of a link coupling gene expression directly to synaptic plasticity.