Modelling of DARPP-32 regulation to understand intracellular signaling in psychiatric disease.
The majority of psychopharmaca acts by binding to G-protein coupled receptors and thereby asserts it's action through the regulation of intracellular signaling networks. The convergence and interactions of pathways within these networks make the detailed signaling hard to study experimentally, and the response to a stimuli can be non-intuitive. To approach these problems with systems biology and merging biochemical data in a computer model to do virtual experiments with high time-resolution can shed new light on the functioning of these networks. The phosphoprotein DARPP-32 is regulated by several modulatory neurotransmitters, including dopamine, serotonin and adenosin, and it's function has been proposed to be altered in schizophrenia. Moreover, the well studied regulation of DARPP-32, and the vast amount of biochemical data makes it a model molecule when it comes to intracellular signaling. To better understand the interactions of the pathways that regulate DARPP-32 activation we constructed a computer model based on experimental data. In this work we discovered unexpected responses of DARPP-32 at fast timescales. An equally important outcome of the work was to identify areas where additional work is needed in order to understand intracellular signaling at the systems level, showing the need for close collaborations between theoretical and experimental biologists.
Lindskog
M
M
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. mia.lindskog@ki.se