Journal article
Control of beta AR- and N-methyl-D-aspartate (NMDA) Receptor-Dependent cAMP Dynamics in Hippocampal Neurons
PLoS computational biology, Vol.12(2), pp.e1004735-e1004735
02/01/2016
DOI: 10.1371/journal.pcbi.1004735
PMCID: PMC4763502
PMID: 26901880
Abstract
Norepinephrine, a neuromodulator that activates beta-adrenergic receptors (beta ARs), 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 beta ARs and N-methyl-D-aspartate receptors (NMDARs). To understand the mechanisms mediating the interactions between beta AR 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 beta AR 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 beta AR-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 beta ARs as well as Gi inhibition of type 1 adenylyl cyclase may underlie the experimental observations. This suggests that signaling by beta-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.
Details
- Title: Subtitle
- Control of beta AR- and N-methyl-D-aspartate (NMDA) Receptor-Dependent cAMP Dynamics in Hippocampal Neurons
- Creators
- Andrew Chay - George Mason UniversityIlaria Zamparo - Veneto Institute of Molecular MedicineAndreas Koschinski - University of OxfordManuela Zaccolo - University of OxfordKim T. Blackwell - George Mason University
- Resource Type
- Journal article
- Publication Details
- PLoS computational biology, Vol.12(2), pp.e1004735-e1004735
- DOI
- 10.1371/journal.pcbi.1004735
- PMID
- 26901880
- PMCID
- PMC4763502
- NLM abbreviation
- PLoS Comput Biol
- ISSN
- 1553-734X
- eISSN
- 1553-7358
- Publisher
- Public Library Science
- Number of pages
- 32
- Grant note
- R01-AA018060 / National Institute on Alcohol Abuse and Alcoholism, through the joint NSF-NIH program on Collaborative Research in Computational Neuroscience R01AA018060 / NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Alcohol Abuse & Alcoholism (NIAAA)
- Language
- English
- Date published
- 02/01/2016
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Iowa Neuroscience Institute
- Record Identifier
- 9984446069802771
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