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The regulatory role of NO-PKG in the cerebellar long-term depression

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Introduction

Long-term depression (LTD) is a persistent decrease in the efficacy of synaptic transmission that results from the removal of AMPA receptors (AMPARs) from the postsynaptic cellular membrane [1]. In Purkinje cells, LTD can be induced by increasing the postsynaptic calcium concentration ([Ca2+]) using flash photolysis of caged Ca2+ [2], which indicates that other second messengers are not fundamental to the occurrence of LTD. However, recent experimental data pointed out that nitric oxide (NO)- cGMP-dependent protein kinase (PKG) pathway can act upstream of Ca2+-signals to regulate Ca2+-induced LTD To gain insights on the biochemical mechanisms involved in this process, we built a computational model to simulate the cerebellar LTD.

Methods

The model consists of a biochemical network composed by the principal pathways involved in the LTD (NO-PKG, conventional protein kinase C (PKC) pathway, and mitogen-activated protein kinase (MAPK) pathway). NO-PKG pathway has two targets in our model: inositol 1,4,5-trisphosphate receptor (IP3R) and G substrate. PKG phosphorylates IP3R causing an increase in its affinity for IP3 [3]. Furthermore, PKG phosphorylates G substrate promoting its binding to protein phosphatase 2A (PP2A), which inhibits its activity. All those biochemical reactions were adapted from previous theoretical works [2, 4, 5] or were constructed according to experimental data. The model was implemented with the program STEPS.

Results and discussion

As an initial stage of our work, we simulated LTD induced by flash photolysis of caged Ca2+ and our results show a correlation between the magnitude of LTD and the amplitude of the postsynaptic [Ca2+], as has been demonstrated previously [1]. To verify the role of NO-PKG pathway in this situation, we simulated the presence of a NO donor (spermine NONOate) while uncaging Ca2+, and our results indicate that NO-PKG pathway decrease the half-maximum [Ca2+] required to induce LTD. We simulated the inhibition of PKG under the same condition, and, during this situation, the alteration in the half-maximum [Ca2+] concentration was not observed. Additionally, we were able to inhibit systematically the catalytic action of PKG on IP3R and G substrate, and our results indicate that both phosphorylations are important to the regulatory role of NO-PKG pathway in the cerebellar LTD. We have similar results to LTD induced by synaptic activity. As a conclusion, our results pointed out that although cerebellar LTD can be induced only by increasing postsynaptic [Ca2+], NO-PKG pathway modulates this process through its action on IP3R and PP2A activity.

References

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    Derkach VA, Oh MC, Guire ES, Soderling TR: Regulatory mechanisms of AMPA receptors in synaptic plasticity. Nat Rev Neurosci. 2007, 8: 101-113. 10.1038/nrn2055.

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    Tanaka K, Khiroug L, Santamaria F, Doi T, Ogasawara H, Ellis-Davies GCR, Augustine GJ: Ca2+ requirements for cerebellar long-term synaptic depression: role for a postsynaptic leaky integrator. Neuron. 2007, 54: 787-800. 10.1016/j.neuron.2007.05.014.

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    Guihard G, Combettes L, Capiod T: 3':5'-cyclic guanosine monophsphate (cGMP) potentiates the inositol 1,4,5-trisphosphate-evoked Ca2+ release inguinea-pig hepatocytes. Biochem J. 1996, 318: 849-855.

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    Doi T, Kuroda S, Michikawa T, Kawato M: Inositol 1,4,5-trisphosphate-dependent Ca2+ threshold dynamics detect spikes timing in cerebellar Purkinje cells. J Neurosci. 2005, 25: 950-961. 10.1523/JNEUROSCI.2727-04.2005.

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    Kuroda S, Schweighofer N, Kawato M: Exploration of signal transduction pathways in cerebellar long-term depression by kinetics simulation. J Neurosci. 2001, 21: 5693-5702.

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Acknowledgements

We thank Keiko Tanaka and George Augustine for sharing their data.

Author information

Correspondence to Gabriela Antunes.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Keywords

  • Nitric Oxide
  • Purkinje Cell
  • AMPA Receptor
  • Flash Photolysis
  • Recent Experimental Data