Gravin orchestrates protein kinase A and β2-adrenergic receptor signaling critical for synaptic plasticity and memory.

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TitleGravin orchestrates protein kinase A and β2-adrenergic receptor signaling critical for synaptic plasticity and memory.
Publication TypeJournal Article
Year of Publication2012
AuthorsHavekes, R, Canton, DA, Park, AJ, Huang, T, Nie, T, Day, JP, Guercio, LA, Grimes, Q, Luczak, V, Gelman, IH, Baillie, GS, Scott, JD, Abel, T
JournalJ Neurosci
Volume32
Issue50
Pagination18137-49
Date Published2012 Dec 12
ISSN1529-2401
KeywordsA Kinase Anchor Proteins, Animals, Blotting, Western, Cell Cycle Proteins, Cyclic AMP-Dependent Protein Kinases, Electric Stimulation, Female, Hippocampus, Immunohistochemistry, Immunoprecipitation, In Situ Hybridization, Male, Maze Learning, Memory, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Neuronal Plasticity, Real-Time Polymerase Chain Reaction, Receptors, Adrenergic, beta-2, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction
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.

DOI10.1523/JNEUROSCI.3612-12.2012
Alternate JournalJ. Neurosci.
PubMed ID23238728
PubMed Central IDPMC3533251
Grant ListR01 AA18060 / AA / NIAAA NIH HHS / United States
G0600765 / / Medical Research Council / United Kingdom
R37 GM048231 / GM / NIGMS NIH HHS / United States
R01 CA094108 / CA / NCI NIH HHS / United States
R01 AA018060 / AA / NIAAA NIH HHS / United States
GM-48231 / GM / NIGMS NIH HHS / United States
R01 GM048231 / GM / NIGMS NIH HHS / United States
T32 GM007517 / GM / NIGMS NIH HHS / United States
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