Data/hora: 03/06/2024 01:08:37

Provedor de dados: 	17	
País: 	United Kingdom	
Título: 	DARPP-32 is a robust integrator of dopamine and glutamate signals	
Autores: 	Nicolas Le Novere; Eric Fernandez; Renaud Schiappa; Jean-Antoine Girault.	
Data: 	2006-11-30	
Ano: 	2006	
Palavras-chave: 	Neuroscience.	
Resumo: 	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 Ca2+ signals. Dynamic simulations allowed to observe the temporal relationships between cAMP and Ca2+ signals. We confirmed that the proposed regulation of protein phosphatase-2A (PP2A) by calcium can account for the observed decrease of Threonine 75 phosphorylation upon glutamate receptor activation. Sensitivity analysis showed that CDK5 activity is a major regulator of the response, as previously suggested. Conversely, the regulation of PP2A by PKA or by calcium, had little effect on the function of DARPP-32 in these conditions. The simulations showed that DARPP-32 is not only a robust signal integrator, but also a coincidence detector, the delay between cAMP and calcium signals affecting the response to the latter. This integration did not depend on the concentration of DARPP-32, while the absolute response on PP1 varied linearly. In silico mutants showed that Ser137 phosphorylation affects the coincidence detector function, and that constitutive phosphorylation in Ser137 transforms DARPP-32 in a quasi-irreversible switch. This work is a first attempt to better understand the complex interactions between cAMP and Ca2+ regulation of DARPP-32. Progressive inclusion of additional components should lead to a realistic model of signalling networks underlying the function of striatal neurons.	
Tipo: 	Poster	
Identificador: 	http://precedings.nature.com/documents/9/version/1

oai:nature.com:10.1038/npre.2006.9.1

http://dx.doi.org/10.1038/npre.2006.9.1	
Fonte: 	Nature Precedings	
Fonte: 	Creative Commons Attribution 3.0 License