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Switch-like PKA responses in the nucleus of striatal neurons
Sorbonne Univ, CNRS, Biol Adaptat & Ageing, F-75005 Paris, France..
KTH, School of Computer Science and Communication (CSC). KTH, Centres, Science for Life Laboratory, SciLifeLab. Tata Inst Fundamental Res, Natl Ctr Biol Sci, Bangalore 560065, Karnataka, India.;Manipal Univ, Manipal 576104, Karnataka, India.;Univ Zurich, Inst Mol Life Sci, Winterthurerstr 190, CH-8057 Zurich, Switzerland..ORCID iD: 0000-0002-1952-9583
KTH, School of Computer Science and Communication (CSC). KTH, Centres, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Neurosci, S-17177 Solna, Sweden..ORCID iD: 0000-0002-0550-0739
Sorbonne Univ, CNRS, Biol Adaptat & Ageing, F-75005 Paris, France..ORCID iD: 0000-0002-8479-1908
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2018 (English)In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 131, no 14, article id UNSP jcs216556Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Company of Biologists Ltd , 2018. Vol. 131, no 14, article id UNSP jcs216556
Keywords [en]
Protein kinase A, Biosensor imaging, Modeling, Nucleus, Signal integration
National Category
Cell Biology
Identifiers
URN: urn:nbn:se:kth:diva-235141DOI: 10.1242/jcs.216556ISI: 000443435600009PubMedID: 29967033Scopus ID: 2-s2.0-85050756664OAI: oai:DiVA.org:kth-235141DiVA, id: diva2:1249687
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscienceEU, Horizon 2020, 720270
Note

QC 20180920

Available from: 2018-09-20 Created: 2018-09-20 Last updated: 2018-09-20Bibliographically approved

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Nair, Anu G.Hellgren Kotaleski, Jeanette

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