title: Control of βAR- and N-methyl-D-aspartate (NMDA) Receptor-Dependent cAMP Dynamics in Hippocampal Neurons.
abstract: Norepinephrine, a neuromodulator that activates β-adrenergic receptors (βARs), facilitates learning and memory as well as the induction of synaptic plasticity in the hippocampus. Several forms of long-term potentiation (LTP) at the Schaffer collateral CA1 synapse require stimulation of both βARs and N-methyl-D-aspartate receptors (NMDARs). To understand the mechanisms mediating the interactions between βAR and NMDAR signaling pathways, we combined FRET imaging of cAMP in hippocampal neuron cultures with spatial mechanistic modeling of signaling pathways in the CA1 pyramidal neuron. Previous work implied that cAMP is synergistically produced in the presence of the βAR agonist isoproterenol and intracellular calcium. In contrast, we show that when application of isoproterenol precedes application of NMDA by several minutes, as is typical of βAR-facilitated LTP experiments, the average amplitude of the cAMP response to NMDA is attenuated compared with the response to NMDA alone. Models simulations suggest that, although the negative feedback loop formed by cAMP, cAMP-dependent protein kinase (PKA), and type 4 phosphodiesterase may be involved in attenuating the cAMP response to NMDA, it is insufficient to explain the range of experimental observations. Instead, attenuation of the cAMP response requires mechanisms upstream of adenylyl cyclase. Our model demonstrates that Gs-to-Gi switching due to PKA phosphorylation of βARs as well as Gi inhibition of type 1 adenylyl cyclase may underlie the experimental observations. This suggests that signaling by β-adrenergic receptors depends on temporal pattern of stimulation, and that switching may represent a novel mechanism for recruiting kinases involved in synaptic plasticity and memory.
authors.affiliation: Molecular Neuroscience Department, Krasnow Institute, George Mason University, Fairfax, Virginia, United States of America.
authors.forename: Andrew
authors.initials: A
authors.lastname: Chay
authors.affiliation: Venetian Institute of Molecular Medicine, Padova, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Zamparo
authors.affiliation: Department of Physiology, Anatomy and Genetics, Oxford University, Oxford, United Kingdom.
authors.forename: Andreas
authors.initials: A
authors.lastname: Koschinski
authors.affiliation: Department of Physiology, Anatomy and Genetics, Oxford University, Oxford, United Kingdom.
authors.forename: Manuela
authors.initials: M
authors.lastname: Zaccolo
authors.affiliation: Molecular Neuroscience Department, Krasnow Institute, George Mason University, Fairfax, Virginia, United States of America.
authors.forename: Kim T
authors.initials: KT
authors.lastname: Blackwell
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D019295:Computational Biology; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism; D031541:Fluorescence Resonance Energy Transfer; D006624:Hippocampus / Q000737:chemistry / Q000166:cytology* / Q000378:metabolism; D007545:Isoproterenol; D057054:Molecular Imaging; D016202:N-Methylaspartate / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*
chemical_list: D011943:Receptors, Adrenergic, beta; D016202:N-Methylaspartate; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D007545:Isoproterenol; D002118:Calcium