Colocalization of protein kinase A with adenylyl cyclase enhances protein kinase A activity during induction of long-lasting long-term-potentiation
| العنوان: | Colocalization of protein kinase A with adenylyl cyclase enhances protein kinase A activity during induction of long-lasting long-term-potentiation |
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| المؤلفون: | Myungsook Kim, Alan Jung Park, Robbert Havekes, Andrew Chay, Leonardo Antonio Guercio, Rodrigo Freire Oliveira, Ted Abel, Kim T Blackwell |
| المصدر: | PLoS Computational Biology PLoS Computational Biology, Vol 7, Iss 6, p e1002084 (2011) |
| سنة النشر: | 2011 |
| مصطلحات موضوعية: | Cell signaling, Dopamine, Long-Term Potentiation, A Kinase Anchor Proteins, AMPA receptor, Biology, Models, Biological, Substrate Specificity, Adenylyl cyclase, Diffusion, 03 medical and health sciences, Cellular and Molecular Neuroscience, chemistry.chemical_compound, Mice, 0302 clinical medicine, Genetics, Cyclic AMP, Animals, Computer Simulation, Protein kinase A, Molecular Biology, lcsh:QH301-705.5, CA1 Region, Hippocampal, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, 0303 health sciences, Stochastic Processes, Ecology, Pyramidal Cells, Colforsin, Proteins, Computational Biology, Long-term potentiation, Synaptic Potentials, Cyclic AMP-Dependent Protein Kinases, Cell biology, Computational Theory and Mathematics, chemistry, lcsh:Biology (General), Modeling and Simulation, Synaptic plasticity, Calcium, Signal transduction, 030217 neurology & neurosurgery, Adenylyl Cyclases, Research Article, Neuroscience |
| الوصف: | 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. Author Summary The hippocampus is a part of the cerebral cortex involved in formation of certain types of long term memories. Activity-dependent change in the strength of neuronal connections in the hippocampus, known as synaptic plasticity, is one mechanism used to store memories. The ability to form crisp and distinguishable memories of different events implies that learning produces plasticity of specific and distinct subsets of synapses within each neuron. Synaptic activity leads to production of intracellular signaling molecules, which ultimately cause changes in the properties of the synapses. The requirement for synaptic specificity seems incompatible with the diffusibility of intracellular signaling molecules. Anchoring proteins restrict signaling molecules to particular subcellular compartments thereby combating the indiscriminate spread of intracellular signaling molecules. To investigate whether the critical function of anchoring proteins is to localize proteins near their activators or their targets, we developed a stochastic reaction-diffusion model of signaling pathways leading to synaptic plasticity in hippocampal neurons. Simulations demonstrate that colocalizing proteins with their activator molecules is more important due to inactivation mechanisms that limit the spatial extent of the activator molecules. |
| تدمد: | 1553-7358 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::ca8b209fd804ff59d37556a1842864a6Test https://pubmed.ncbi.nlm.nih.gov/21738458Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....ca8b209fd804ff59d37556a1842864a6 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15537358 |
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