Journal article
Subcellular Location of PKA Controls Striatal Plasticity: Stochastic Simulations in Spiny Dendrites
PLoS computational biology, Vol.8(2), pp.e1002383-e1002383
02/01/2012
DOI: 10.1371/journal.pcbi.1002383
PMCID: PMC3276550
PMID: 22346744
Abstract
Dopamine release in the striatum has been implicated in various forms of reward dependent learning. Dopamine leads to production of cAMP and activation of protein kinase A (PKA), which are involved in striatal synaptic plasticity and learning. PKA and its protein targets are not diffusely located throughout the neuron, but are confined to various subcellular compartments by anchoring molecules such as A-Kinase Anchoring Proteins (AKAPs). Experiments have shown that blocking the interaction of PKA with AKAPs disrupts its subcellular location and prevents LTP in the hippocampus and striatum; however, these experiments have not revealed whether the critical function of anchoring is to locate PKA near the cAMP that activates it or near its targets, such as AMPA receptors located in the post-synaptic density. We have developed a large scale stochastic reaction-diffusion model of signaling pathways in a medium spiny projection neuron dendrite with spines, based on published biochemical measurements, to investigate this question and to evaluate whether dopamine signaling exhibits spatial specificity post-synaptically. The model was stimulated with dopamine pulses mimicking those recorded in response to reward. Simulations show that PKA colocalization with adenylate cyclase, either in the spine head or in the dendrite, leads to greater phosphorylation of DARPP-32 Thr34 and AMPA receptor GluA1 Ser845 than when PKA is anchored away from adenylate cyclase. Simulations further demonstrate that though cAMP exhibits a strong spatial gradient, diffusible DARPP-32 facilitates the spread of PKA activity, suggesting that additional inactivation mechanisms are required to produce spatial specificity of PKA activity.
Details
- Title: Subtitle
- Subcellular Location of PKA Controls Striatal Plasticity: Stochastic Simulations in Spiny Dendrites
- Creators
- Rodrigo F. Oliveira - George Mason UniversityMyungSook Kim - George Mason UniversityKim T. Blackwell - George Mason University
- Resource Type
- Journal article
- Publication Details
- PLoS computational biology, Vol.8(2), pp.e1002383-e1002383
- DOI
- 10.1371/journal.pcbi.1002383
- PMID
- 22346744
- PMCID
- PMC3276550
- NLM abbreviation
- PLoS Comput Biol
- ISSN
- 1553-734X
- eISSN
- 1553-7358
- Publisher
- Public Library Science
- Number of pages
- 19
- Grant note
- R01AA016022 / 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) MURI N00014-10-1-0198 / ONR; Office of Naval Research RO1AA-16022 / NSF-NIH through NIH
- Language
- English
- Date published
- 02/01/2012
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Iowa Neuroscience Institute
- Record Identifier
- 9984446513502771
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