title: Gravin orchestrates protein kinase A and β2-adrenergic receptor signaling critical for synaptic plasticity and memory.
abstract: A kinase-anchoring proteins (AKAPs) organize compartmentalized pools of protein kinase A (PKA) to enable localized signaling events within neurons. However, it is unclear which of the many expressed AKAPs in neurons target PKA to signaling complexes important for long-lasting forms of synaptic plasticity and memory storage. In the forebrain, the anchoring protein gravin recruits a signaling complex containing PKA, PKC, calmodulin, and PDE4D (phosphodiesterase 4D) to the β2-adrenergic receptor. Here, we show that mice lacking the α-isoform of gravin have deficits in PKA-dependent long-lasting forms of hippocampal synaptic plasticity including β2-adrenergic receptor-mediated plasticity, and selective impairments of long-term memory storage. Furthermore, both hippocampal β2-adrenergic receptor phosphorylation by PKA, and learning-induced activation of ERK in the CA1 region of the hippocampus are attenuated in mice lacking gravin-α. We conclude that gravin compartmentalizes a significant pool of PKA that regulates learning-induced β2-adrenergic receptor signaling and ERK activation in the hippocampus in vivo, thereby organizing molecular interactions between glutamatergic and noradrenergic signaling pathways for long-lasting synaptic plasticity, and memory storage.
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6018, USA. havekesr@sas.upenn.edu
authors.forename: Robbert
authors.initials: R
authors.lastname: Havekes
authors.forename: David A
authors.initials: DA
authors.lastname: Canton
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Park
authors.forename: Ted
authors.initials: T
authors.lastname: Huang
authors.forename: Ting
authors.initials: T
authors.lastname: Nie
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Day
authors.forename: Leonardo A
authors.initials: LA
authors.lastname: Guercio
authors.forename: Quinn
authors.initials: Q
authors.lastname: Grimes
authors.forename: Vincent
authors.initials: V
authors.lastname: Luczak
authors.forename: Irwin H
authors.initials: IH
authors.lastname: Gelman
authors.forename: George S
authors.initials: GS
authors.lastname: Baillie
authors.forename: John D
authors.initials: JD
authors.lastname: Scott
authors.forename: Ted
authors.initials: T
authors.lastname: Abel
mesh_terms: D054758:A Kinase Anchor Proteins / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004558:Electric Stimulation; D005260:Female; D006624:Hippocampus / Q000502:physiology; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D017403:In Situ Hybridization; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008568:Memory / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009473:Neuronal Plasticity / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D054758:A Kinase Anchor Proteins; C491161:Akap12 protein, mouse; D018797:Cell Cycle Proteins; D018343:Receptors, Adrenergic, beta-2; D017868:Cyclic AMP-Dependent Protein Kinases