ABSTRACT
Although it is known that protein kinase A (PKA) in the nucleus regulates gene expression, the specificities of nuclear PKA signaling remain poorly understood. Here, we combined computational modeling and live-cell imaging of PKA-dependent phosphorylation in mouse brain slices to investigate how transient dopamine signals are translated into nuclear PKA activity in cortical pyramidal neurons and striatal medium spiny neurons. We observed that the nuclear PKA signal in striatal neurons featured an ultrasensitive responsiveness, associated with fast all-or-none responses, which is not consistent with the commonly accepted theory of a slow and passive diffusion of catalytic PKA in the nucleus. Our numerical model suggests that a positive feed-forward mechanism inhibiting nuclear phosphatase activity – possibly mediated by DARPP-32 (also known as PPP1R1B) – could be responsible for this non-linear pattern of nuclear PKA response, allowing for a better detection of the transient dopamine signals that are often associated with reward-mediated learning.
Footnotes
Author contributions
Conceptualization: C.Y., A.G.N., P.V., L.R.V.C.; Methodology: A.G.N., P.V., L.R.V.C.; Software: A.G.N., P.V.; Validation: C.Y., A.G.N., P.V., L.R.V.C.; Formal analysis: C.Y., A.G.N.; Investigation: C.Y., L.R.V.C.; Data curation: P.V., L.R.V.C.; Writing - original draft: C.Y., A.G.N., P.V., L.R.V.C.; Writing - review & editing: C.Y., A.G.N., P.V., L.R.V.C.; Visualization: C.Y., P.V., L.R.V.C.; Supervision: J.H.K., P.V., L.R.V.C.; Project administration: P.V.; Funding acquisition: J.H.K., P.V.
Funding
This work was funded by ‘DIM Cerveau et Pensée IdF 2014’, the Association France Parkinson, the European Horizon 2020 Framework Program under grant agreement no. 720270 (Human Brain Project SGA1) and EuroSPIN – an Erasmus Mundus Joint Doctoral program. This work was supported by the Investissements d'Avenir program managed by the Agence Nationale de la Recherche (ANR) under reference ANR-11-IDEX-0004-02.
