
@article {38424,
	title = {Switch-like PKA responses in the nucleus of striatal neurons.},
	journal = {J Cell Sci},
	year = {2018},
	month = {2018 Jul 02},
	abstract = {<p>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 - 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.</p>
},
	issn = {1477-9137},
	doi = {10.1242/jcs.216556},
	author = {Yapo, Cedric and Nair, Anu G and Hellgren Kotaleski, Jeanette and Vincent, Pierre and Castro, Liliana R V}
}
@article {21469,
	title = {Detection of phasic dopamine by D1 and D2 striatal medium spiny neurons.},
	journal = {J Physiol},
	year = {2017},
	month = {2017 Aug 07},
	abstract = {<p>The phasic release of dopamine in the striatum determines various aspects of reward and action selection, but the dynamics of dopamine effect on intracellular signalling remains poorly understood. We used genetically-encoded FRET biosensors in striatal brain slices to quantify the effect of transient dopamine on cAMP or PKA-dependent phosphorylation level, and computational modelling to further explore the dynamics of this signalling pathway. Medium-sized spiny neurons (MSNs), which express either D1 or D2 dopamine receptors, responded to dopamine by an increase or a decrease in cAMP, respectively. Transient dopamine showed similar sub-micromolar efficacies on cAMP in both D1 and D2 MSNs, thus challenging the commonly accepted notion that dopamine efficacy is much higher on D2 than on D1 receptors. However, in D2 MSNs, the large decrease in cAMP level triggered by transient dopamine did not translate in a decrease in PKA-dependent phosphorylation level, owing to the efficient inhibition of Protein Phosphatase 1 by DARPP-32. Simulations further suggested that D2 MSNs can also operate in a "tone-sensing" mode, allowing them to detect transient dips in basal dopamine. Overall, our results show that D2 MSNs may sense much more complex patterns of dopamine than previously thought. This article is protected by copyright. All rights reserved.</p>
},
	issn = {1469-7793},
	doi = {10.1113/JP274475},
	author = {Yapo, Cedric and Nair, Anu G and Clement, Lorna and Castro, Liliana R and Hellgren Kotaleski, Jeanette and Vincent, Pierre}
}
