Neuroscience 2002 Abstract
| Presentation Number: | 832.2 |
|---|---|
| Abstract Title: | A kinetic model of DARPP-32 and the PKA/PP1 cascade. |
| Authors: |
Lindskog, M.*1
; Blackwell, K. T.2
; Wikstrom, M. A.3
; Hellgren Kotaleski, J.1
1NADA, Kungliga Tekniska H÷gskolan, Stockholm, Sweden 2Neuroscience, Karolinska Institutet, Stockholm, Sweden 3Krasnow Institute and School of Computational Sciences, George MasonUniversity, Fairfax, VA |
| Primary Theme and Topics |
Synaptic Transmission and Excitability - Intracellular Signalling Pathways -- Protein phosphorylation |
| Session: |
832. Synaptic transmission: protein phosphorylation III Poster |
| Presentation Time: | Thursday, November 7, 2002 9:00 AM-10:00 AM |
| Location: | Hall A2-B3 C-67 |
| Keywords: | striatum, calcium, phosphorylation, computer modeling |
Intracellular signaling through biochemical pathways allows cells to integrate and process information. The interactions between the components of the signaling pathways can give non-intuitive responses to inputs. In spiny projection neurons of the striatum, the cAMP dependent protein kinase (PKA) cascade is modulated by the phosphoprotein DARPP-32, which can either potentiate or attenuate the effect of PKA, depending on the site of phosphorylation. We have made a kinetic model of the bimolecular and enzyme reactions of the PKA cascade. Rate constants for the specific reactions are taken from experimental data. The model includes DARPP-32 phosphorylation at threonine (Thr) 34 and 75 by PKA and cdk5, respectively, and dephosphorylated by protein phosphatase (PP) 2B and 2A, respectively. The upstream regulation of these enzymes includes the G-protein cycle, Ca2+ influx, activation of Ca2+/calmodulin, cAMP formation and cdk5 activation. PhosphoThr34-DARPP-32 inhibits PP1, whereas PhosphoThr75-DARPP-32 inhibits PKA. To evaluate the role of DARPP-32 in the PKA cascade, we measure the phosphorylation of a hypothetical substrate that is phosphorylated by PKA and dephosphorylated by PP1.
This model shows that DARPP-32 slows down the activity of the PKA cascade, making the increase of phosphorylation of the substrate following cAMP stimulation longe lasting compared to a cascade where DARPP-32 is omitted. These results fit well with experimental data and have important implications for temporal summation of inputs.
This model shows that DARPP-32 slows down the activity of the PKA cascade, making the increase of phosphorylation of the substrate following cAMP stimulation longe lasting compared to a cascade where DARPP-32 is omitted. These results fit well with experimental data and have important implications for temporal summation of inputs.
Supported by VR-NT 621-2001-1496 and Knut and Alice Wallenbergs Foundation
Sample Citation:
[Authors]. [Abstract Title]. Program No. XXX.XX. 2002 Neuroscience Meeting Planner. Orlando, FL: Society for Neuroscience, 2002. Online.
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