Protein kinase M zeta synthesis from a brain mRNA encoding an independent protein kinase C zeta catalytic domain. Implications for the molecular mechanism of memory.
Protein kinase M zeta (PKM zeta) 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. PKM zeta is the independent catalytic domain of the atypical PKC zeta isoform and produces long term effects at synapses because it is persistently active, lacking autoinhibition from the regulatory domain of PKC zeta. PKM has been thought of as a proteolytic fragment of PKC. Here we report that brain PKM zeta is a new PKC isoform, synthesized from a PKM zeta mRNA encoding a PKC zeta catalytic domain without a regulatory domain. Multiple zeta-specific antisera show that PKM zeta is expressed in rat forebrain as the major form of zeta in the near absence of full-length PKC zeta. A PKC zeta knockout mouse, in which the regulatory domain was disrupted and catalytic domain spared, still expresses brain PKM zeta, indicating that this form of PKM is not a PKC zeta proteolytic fragment. Furthermore, the distribution of brain PKM zeta does not correlate with PKC zeta mRNA but instead with an alternate zeta RNA transcript thought incapable of producing protein. In vitro translation of this RNA, however, generates PKM zeta of the same molecular weight as that in brain. Metabolic labeling of hippocampal slices shows increased de novo synthesis of PKM zeta in LTP. Because PKM zeta 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.
Hernandez
A Ivan
AI
Department of Physiology, State University of New York Downstate Medical Center, Brooklyn, 11203, USA.
Blace
Nancy
N
Crary
John F
JF
Serrano
Peter A
PA
Leitges
Michael
M
Libien
Jenny M
JM
Weinstein
Gila
G
Tcherapanov
Andrew
A
Sacktor
Todd Charlton
TC
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000201:enzymology*; D020134:Catalytic Domain / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000502:physiology; D008297:Male; D008568:Memory / Q000502:physiology*; D051379:Mice; D008959:Models, Neurological; D008969:Molecular Sequence Data; D009473:Neuronal Plasticity; D014176:Protein Biosynthesis; D011493:Protein Kinase C / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics*; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012689:Sequence Homology, Nucleic Acid; D014018:Tissue Distribution; D000099221:Protein Kinase C zeta
D018076:DNA, Complementary; D011493:Protein Kinase C; D012333:RNA, Messenger; D000099221:Protein Kinase C zeta