The role of type 4 phosphodiesterases in generating microdomains of cAMP: Large scale stochastic simulations

Oliveira, R.F., Terrin, A., Di Benedetto, G., Cannon, R.C., Koh, K., Kim, M., Zaccolo, M. and Blackwell, K. (2010) The role of type 4 phosphodiesterases in generating microdomains of cAMP: Large scale stochastic simulations. PLoS ONE, 5(7), e11725. (doi: 10.1371/journal.pone.0011725) (PMID:20661441) (PMCID:PMC2908681)

Abstract

Cyclic AMP (cAMP) and its main effector Protein Kinase A (PKA) are critical for several aspects of neuronal function including synaptic plasticity. Specificity of synaptic plasticity requires that cAMP activates PKA in a highly localized manner despite the speed with which cAMP diffuses. Two mechanisms have been proposed to produce localized elevations in cAMP, known as microdomains: impeded diffusion, and high phosphodiesterase (PDE) activity. This paper investigates the mechanism of localized cAMP signaling using a computational model of the biochemical network in the HEK293 cell, which is a subset of pathways involved in PKA-dependent synaptic plasticity. This biochemical network includes cAMP production, PKA activation, and cAMP degradation by PDE activity. The model is implemented in NeuroRD: novel, computationally efficient, stochastic reaction-diffusion software, and is constrained by intracellular cAMP dynamics that were determined experimentally by real-time imaging using an Epac-based FRET sensor (H30). The model reproduces the high concentration cAMP microdomain in the submembrane region, distinct from the lower concentration of cAMP in the cytosol. Simulations further demonstrate that generation of the cAMP microdomain requires a pool of PDE4D anchored in the cytosol and also requires PKA-mediated phosphorylation of PDE4D which increases its activity. The microdomain does not require impeded diffusion of cAMP, confirming that barriers are not required for microdomains. The simulations reported here further demonstrate the utility of the new stochastic reaction-diffusion algorithm for exploring signaling pathways in spatially complex structures such as neurons.

• Item Type: Articles
• Additional Information: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Zaccolo, Professor Manuela and Terrin, Ms Anna
• Authors: Oliveira, R.F., Terrin, A., Di Benedetto, G., Cannon, R.C., Koh, K., Kim, M., Zaccolo, M., and Blackwell, K.
• College/School: College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience
• Journal Name: PLoS ONE
• Publisher: Public Library of Science
• ISSN: 1932-6203
• ISSN (Online): 1932-6203
• Published Online: 22 July 2010
• Copyright Holders: Copyright © 2010 The Authors
• First Published: First published in PLoS ONE 2010 5(7): e11725
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
46534	1	Role of PDE2 in the control of cardiac myocyte hypertrophy.	Manuela Zaccolo	British Heart Foundation (BHF)	PG/07/091/23698	Institute of Neuroscience and Psychology