Journal article
Colocalization of protein kinase A with adenylyl cyclase enhances protein kinase A activity during induction of long-lasting long-term-potentiation
PLoS computational biology, Vol.7(6), pp.e1002084-e1002084
06/2011
DOI: 10.1371/journal.pcbi.1002084
PMCID: PMC3127802
PMID: 21738458
Abstract
The ability of neurons to differentially respond to specific temporal and spatial input patterns underlies information storage in neural circuits. One means of achieving spatial specificity is to restrict signaling molecules to particular subcellular compartments using anchoring molecules such as A-Kinase Anchoring Proteins (AKAPs). Disruption of protein kinase A (PKA) anchoring to AKAPs impairs a PKA-dependent form of long term potentiation (LTP) in the hippocampus. To investigate the role of localized PKA signaling in LTP, we developed a stochastic reaction-diffusion model of the signaling pathways leading to PKA activation in CA1 pyramidal neurons. Simulations investigated whether the role of anchoring is to locate kinases near molecules that activate them, or near their target molecules. The results show that anchoring PKA with adenylyl cyclase (which produces cAMP that activates PKA) produces significantly greater PKA activity, and phosphorylation of both inhibitor-1 and AMPA receptor GluR1 subunit on S845, than when PKA is anchored apart from adenylyl cyclase. The spatial microdomain of cAMP was smaller than that of PKA suggesting that anchoring PKA near its source of cAMP is critical because inactivation by phosphodiesterase limits diffusion of cAMP. The prediction that the role of anchoring is to colocalize PKA near adenylyl cyclase was confirmed by experimentally rescuing the deficit in LTP produced by disruption of PKA anchoring using phosphodiesterase inhibitors. Additional experiments confirm the model prediction that disruption of anchoring impairs S845 phosphorylation produced by forskolin-induced synaptic potentiation. Collectively, these results show that locating PKA near adenylyl cyclase is a critical function of anchoring.
Details
- Title: Subtitle
- Colocalization of protein kinase A with adenylyl cyclase enhances protein kinase A activity during induction of long-lasting long-term-potentiation
- Creators
- Myungsook Kim - George Mason University, The Krasnow Institute for Advanced Studies, Fairfax, Virginia, United States of AmericaAlan Jung ParkRobbert HavekesAndrew ChayLeonardo Antonio GuercioRodrigo Freire OliveiraTed AbelKim T Blackwell
- Resource Type
- Journal article
- Publication Details
- PLoS computational biology, Vol.7(6), pp.e1002084-e1002084
- DOI
- 10.1371/journal.pcbi.1002084
- PMID
- 21738458
- PMCID
- PMC3127802
- NLM abbreviation
- PLoS Comput Biol
- ISSN
- 1553-734X
- eISSN
- 1553-7358
- Publisher
- United States
- Grant note
- R01 AA18060 / NIAAA NIH HHS R01 AA018060 / NIAAA NIH HHS T32 GM007517 / NIGMS NIH HHS
- Language
- English
- Date published
- 06/2011
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Psychiatry; Psychological and Brain Sciences; Iowa Neuroscience Institute; Neuroscience and Pharmacology; Biochemistry and Molecular Biology
- Record Identifier
- 9984065826102771
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