原创力文档darpp-32 is a robust integrator of dopamine and glutamate signalsdarpp-32是一个健壮的积分器的多巴胺和谷氨酸信号.pdfVIP
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darpp-32 is a robust integrator of dopamine and glutamate signalsdarpp-32是一个健壮的积分器的多巴胺和谷氨酸信号
DARPP-32 Is a Robust Integrator of Dopamine
and Glutamate Signals
´ 1 1 2,3 ` 1*
Eric Fernandez , Renaud Schiappa , Jean-Antoine Girault , Nicolas Le Novere
´
1 EMBL–EBI, Wellcome-Trust Genome Campus, Hinxton, United Kingdom, 2 INSERM U536, Institut du Fer a Moulin, Paris, France, 3 Universite de Pierre et Marie Curie
Integration of neurotransmitter and neuromodulator signals in the striatum plays a central role in the functions and
dysfunctions of the basal ganglia. DARPP-32 is a key actor of this integration in the GABAergic medium-size spiny
neurons, in particular in response to dopamine and glutamate. When phosphorylated by cAMP-dependent protein
kinase (PKA), DARPP-32 inhibits protein phosphatase-1 (PP1), whereas when phosphorylated by cyclin-dependent
kinase 5 (CDK5) it inhibits PKA. DARPP-32 is also regulated by casein kinases and by several protein phosphatases.
These complex and intricate regulations make simple predictions of DARPP-32 dynamic behaviour virtually impossible.
We used detailed quantitative modelling of the regulation of DARPP-32 phosphorylation to improve our
understanding of its function. The models included all the combinations of the three best-characterized
phosphorylation sites of DARPP-32, their regulation by kinases and phosphatases, and the regulation of those
enzymes by cAMP and Ca2þ signals. Dynamic simulations allowed us to observe the temporal relationships between
cAMP and Ca2þ signals. We confirmed that the proposed regulation of protein phosphatase-2A (PP2A) by calcium can
acc
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