Abstract
Synaptic actions of brain-derived neurotrophic factor (BDNF) are 'gated' by cyclic AMP (cAMP), but the underlying molecular mechanisms remain unclear. Here we report that cAMP regulates BDNF function in mature hippocampal neurons by modulating the signaling and trafficking of its receptor TrkB. cAMP gated the TrkB tyrosine kinase with three characteristic features: BDNF-induced TrkB phosphorylation was attenuated by inhibitors of cAMP signaling, it was potentiated by cAMP analogs, and activation of the cAMP pathway alone had no effect. In addition, cAMP facilitated trafficking of TrkB to dendritic spines, possibly by promoting its interaction with synaptic scaffolding protein PSD-95. Norepinephrinergic and dopaminergic agonists, which elevate intracellular cAMP concentration, also enhanced TrkB phosphorylation and its translocation to spines. cAMP gated long-term modulation by BDNF of spine density, but not the number of primary dendrites. These results reveal a specific role of cAMP in controlling BDNF actions in the brain, and provide new insights into the molecular mechanism underlying cAMP gating.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / pharmacology
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Adrenergic beta-Agonists / pharmacology
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Amino Acids
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Analysis of Variance
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Animals
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Animals, Newborn
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Blotting, Western / methods
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Brain-Derived Neurotrophic Factor / pharmacology*
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Carbazoles / pharmacology
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Cell Count / methods
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Cells, Cultured
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Colforsin / pharmacology
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Cyclic AMP / analogs & derivatives*
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Cyclic AMP / pharmacology
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Cyclic AMP / physiology*
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Dendritic Spines / drug effects*
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Dendritic Spines / physiology
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Disks Large Homolog 4 Protein
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Dopamine Agonists
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Dose-Response Relationship, Drug
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Drug Interactions
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Electric Stimulation / methods
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Electrophysiology / methods
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Enzyme Inhibitors / pharmacology
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Excitatory Postsynaptic Potentials / drug effects
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Excitatory Postsynaptic Potentials / radiation effects
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Fluorescent Antibody Technique / methods
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Gene Expression Regulation
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Green Fluorescent Proteins / metabolism
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Hippocampus / cytology*
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Immunoprecipitation / methods
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In Vitro Techniques
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Indoles / pharmacology
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Intracellular Signaling Peptides and Proteins
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Isoproterenol / pharmacology
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Membrane Proteins
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Microtubule-Associated Proteins / metabolism
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Nerve Tissue Proteins / metabolism
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Neurons / cytology*
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Neurons / physiology
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Phosphorylation / drug effects
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Protein Kinase Inhibitors / pharmacology
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Pseudopodia / drug effects
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Pyrroles / pharmacology
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Rats
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Receptor, trkB / metabolism*
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Thionucleotides / pharmacology
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Transfection / methods
Substances
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Adrenergic beta-Agonists
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Amino Acids
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Brain-Derived Neurotrophic Factor
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Carbazoles
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Disks Large Homolog 4 Protein
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Dlg4 protein, rat
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Dopamine Agonists
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Enzyme Inhibitors
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Indoles
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Intracellular Signaling Peptides and Proteins
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MAP2 protein, rat
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Membrane Proteins
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Microtubule-Associated Proteins
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Nerve Tissue Proteins
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Protein Kinase Inhibitors
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Pyrroles
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Thionucleotides
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dolaisoleucine
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postsynaptic density proteins
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Green Fluorescent Proteins
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Colforsin
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adenosine-3',5'-cyclic phosphorothioate
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KT 5720
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2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine
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Cyclic AMP
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Receptor, trkB
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Isoproterenol