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The Journal of Neuroscience, March 14, 2007, 27(11):2744-2750; doi:10.1523/JNEUROSCI.5352-06.2007

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Cellular/Molecular
Dynamics of Protein Kinase A Signaling at the Membrane, in the Cytosol, and in the Nucleus of Neurons in Mouse Brain Slices

Nicolas Gervasi,^1,2 Régine Hepp,^1,2 Ludovic Tricoire,^1,2 Jin Zhang,^3,4 Bertrand Lambolez,^1,2 Danièle Paupardin-Tritsch,^1,2 and Pierre Vincent^1,2

¹Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7102, and ²Université Pierre et Marie Curie-Paris 6, Unité Mixte de Recherche 7102, F-75005 Paris, France, and ³Departments of Pharmacology and Molecular Sciences and ⁴Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

Correspondence should be addressed to Dr. Pierre Vincent, Unité Mixte de Recherche 7102, Neurobiologie des Processus Adaptatifs, Université Pierre et Marie Curie-Paris6, 9, quai St. Bernard, 75005 Paris, France. Email: pierre.vincent{at}snv.jussieu.fr

The cAMP-dependent protein kinase A (PKA) plays a ubiquitous role in the regulation of neuronal activity, but the dynamics of its activation have been difficult to investigate. We used the genetically encoded fluorescent probe AKAR2 to record PKA activation in the cytosol and the nucleus of neurons in mouse brain slice preparations, whereas the potassium current underlying the slow afterhyperpolarization potential (sAHP) in thalamic intralaminar neurons was used to monitor PKA activation at the membrane. Adenylyl cyclase was stimulated either directly using forskolin or via activation of 5-HT₇ receptors. Both stimulations produced a maximal effect on sAHP, whereas in the cytosol, the amplitude of the 5-HT₇ receptor-mediated response was half of that after direct adenylyl cyclase stimulation with forskolin. 5-HT₇-mediated PKA responses were obtained in 30 s at the membrane, in 2.5 min in the cytosol, and in 13 min in the nucleus. Our results show in morphologically intact mammalian neurons the potential physiological relevance of PKA signal integration at the subcellular level: neuromodulators produce fast and powerful effects on membrane excitability, consistent with a highly efficient functional coupling between adenylyl cyclases, PKA, and target channels. Phosphorylation in the cytosol is slower and of graded amplitude, showing a differential integration of the PKA signal between the membrane and the cytosol. The nucleus integrates these cytosolic signals over periods of tens of minutes, consistent with passive diffusion of the free catalytic subunit of PKA into the nucleus, eventually resulting in a graded modulation of gene expression.

Key words: neuromodulation; serotonin; PKA; cyclic AMP; genetically encoded fluorescent probe; FRET

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Received March 8, 2006; revised Jan. 30, 2007; accepted Jan. 30, 2007.

Correspondence should be addressed to Dr. Pierre Vincent, Unité Mixte de Recherche 7102, Neurobiologie des Processus Adaptatifs, Université Pierre et Marie Curie-Paris6, 9, quai St. Bernard, 75005 Paris, France. Email: pierre.vincent{at}snv.jussieu.fr

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