title: An essential role for postsynaptic calmodulin and protein kinase activity in long-term potentiation.
abstract: The phenomenon of long-term potentiation (LTP), a long lasting increase in the strength of synaptic transmission which is due to brief, repetitive activation of excitatory afferent fibres, is one of the most striking examples of synaptic plasticity in the mammalian brain. In the CA1 region of the hippocampus, the induction of LTP requires activation of NMDA (N-methyl-D-aspartate) receptors by synaptically released glutamate with concomitant postsynaptic membrane depolarization. This relieves the voltage-dependent magnesium block of the NMDA-receptor ion channel, allowing calcium to flow into the dendritic spine. Although calcium has been shown to be a necessary trigger for LTP (refs 11, 12), little is known about the immediate biochemical processes that are activated by calcium and are responsible for LTP. The most attractive candidates have been calcium/calmodulin-dependent protein kinase II (CaM-KII) (refs 13-16), protein kinase C (refs 17-19), and the calcium-dependent protease, calpain. Extracellular application of protein kinase inhibitors to the hippocampal slice preparation blocks the induction of LTP (refs 21-23) but it is unclear whether this is due to a pre- and/or postsynaptic action. We have found that intracellular injection into CA1 pyramidal cells of the protein kinase inhibitor H-7, or of the calmodulin antagonist calmidazolium, blocks LTP. Furthermore, LTP is blocked by the injection of synthetic peptides that are potent calmodulin antagonists and inhibit CaM-KII auto- and substrate phosphorylation. These findings demonstrate that in the postsynaptic cell both activation of calmodulin and kinase activity are required for the generation of LTP, and focus further attention on the potential role of CaM-KII in LTP.
authors.affiliation: Department of Psychiatry, University of California, San Francisco 94143.
authors.forename: R C
authors.initials: RC
authors.lastname: Malenka
authors.forename: J A
authors.initials: JA
authors.lastname: Kauer
authors.forename: D J
authors.initials: DJ
authors.lastname: Perkel
authors.forename: M D
authors.initials: MD
authors.lastname: Mauk
authors.forename: P T
authors.initials: PT
authors.lastname: Kelly
authors.forename: R A
authors.initials: RA
authors.lastname: Nicoll
authors.forename: M N
authors.initials: MN
authors.lastname: Waxham
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002147:Calmodulin / Q000502:physiology*; D007546:Isoquinolines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011494:Protein Kinases / Q000502:physiology*; D013569:Synapses / Q000502:physiology*; D009435:Synaptic Transmission
chemical_list: D002147:Calmodulin; D007546:Isoquinolines; D010879:Piperazines; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D011494:Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases