title: Cellular pharmacology of protein kinase Mζ (PKMζ) contrasts with its in vitro profile: implications for PKMζ as a mediator of memory.
abstract: A number of recent studies have used pharmacological inhibitors to establish a role for protein kinase Mζ (PKMζ) in synaptic plasticity and memory. These studies use zeta inhibitory peptide (ZIP) and chelerythrine as inhibitors of PKMζ to block long term potentiation and memory; staurosporine is used as a negative control to show that a nonspecific kinase inhibitor does not block long term potentiation and memory. Here, we show that neither ZIP nor chelerythrine inhibits PKMζ in cultured cells or brain slices. In contrast, staurosporine does block PKMζ activity in cells and brain slices by inhibiting its upstream phosphoinositide-dependent kinase-1. These studies demonstrate that the effectiveness of drugs against purified PKMζ may not be indicative of their specificity in the more complex environment of the cell and suggest that PKMζ is unlikely to be the mediator of synaptic plasticity or memory.
authors.affiliation: Department of Pharmacology, University of California San Diego, La Jolla, California 92093, USA.
authors.forename: Alyssa X
authors.initials: AX
authors.lastname: Wu-Zhang
authors.forename: Cicely L
authors.initials: CL
authors.lastname: Schramm
authors.forename: Sadegh
authors.initials: S
authors.lastname: Nabavi
authors.forename: Roberto
authors.initials: R
authors.lastname: Malinow
authors.forename: Alexandra C
authors.initials: AC
authors.lastname: Newton
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D053119:Benzophenanthridines / Q000494:pharmacology; D019556:COS Cells; D002522:Chlorocebus aethiops; D004791:Enzyme Inhibitors / Q000494:pharmacology; D057809:HEK293 Cells; D006367:HeLa Cells; D006624:Hippocampus / Q000187:drug effects* / Q000201:enzymology*; D006801:Humans; D008568:Memory / Q000502:physiology*; D009473:Neuronal Plasticity / Q000502:physiology; D009924:Organ Culture Techniques; D010455:Peptides / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D019311:Staurosporine / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D053119:Benzophenanthridines; D004791:Enzyme Inhibitors; D010455:Peptides; C016299:chelerythrine; D011493:Protein Kinase C; C504730:protein kinase M zeta, rat; D019311:Staurosporine