title: p21-Activated kinase 3 (PAK3) protein regulates synaptic transmission through its interaction with the Nck2/Grb4 protein adaptor.
abstract: Mutations in the p21-activated kinase 3 gene (pak3) are responsible for nonsyndromic forms of mental retardation. Expression of mutated PAK3 proteins in hippocampal neurons induces abnormal dendritic spine morphology and long term potentiation anomalies, whereas pak3 gene invalidation leads to cognitive impairments. How PAK3 regulates synaptic plasticity is still largely unknown. To better understand how PAK3 affects neuronal synaptic plasticity, we focused on its interaction with the Nck adaptors that play a crucial role in PAK signaling. We report here that PAK3 interacts preferentially with Nck2/Grb4 in brain extracts and in transfected cells. This interaction is independent of PAK3 kinase activity. Selective uncoupling of the Nck2 interactions in acute cortical slices using an interfering peptide leads to a rapid increase in evoked transmission to pyramidal neurons. The P12A mutation in the PAK3 protein strongly decreases the interaction with Nck2 but only slightly with Nck1. In transfected hippocampal cultures, expression of the P12A-mutated protein has no effect on spine morphogenesis or synaptic density. The PAK3-P12A mutant does not affect synaptic transmission, whereas the expression of the wild-type PAK3 protein decreases the amplitude of spontaneous miniature excitatory currents. Altogether, these data show that PAK3 down-regulates synaptic transmission through its interaction with Nck2.
authors.affiliation: CNRS, Institut de Neurobiologie Alfred Fessard, Laboratoire de Neurobiologie Cellulaire et Moléculaire, 91190 Gif sur Yvette, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Thévenot
authors.forename: Alexandre William
authors.initials: AW
authors.lastname: Moreau
authors.forename: Véronique
authors.initials: V
authors.lastname: Rousseau
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Combeau
authors.forename: Florence
authors.initials: F
authors.lastname: Domenichini
authors.forename: Claire
authors.initials: C
authors.lastname: Jacquet
authors.forename: Olivier
authors.initials: O
authors.lastname: Goupille
authors.forename: Muriel
authors.initials: M
authors.lastname: Amar
authors.forename: Patricia
authors.initials: P
authors.lastname: Kreis
authors.forename: Philippe
authors.initials: P
authors.lastname: Fossier
authors.forename: Jean-Vianney
authors.initials: JV
authors.lastname: Barnier
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D019943:Amino Acid Substitution; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D006367:HeLa Cells; D006801:Humans; D020125:Mutation, Missense; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology*; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C485544:NCK2 protein, human; C078332:Nck protein; D015513:Oncogene Proteins; C515911:PAK3 protein, human; D054462:p21-Activated Kinases