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The Journal of Neuroscience, November 8, 2006, 26(45):11670-11681; doi:10.1523/JNEUROSCI.3321-06.2006

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Cellular/Molecular
Protein Kinase A-Mediated Synapsin I Phosphorylation Is a Central Modulator of Ca²⁺-Dependent Synaptic Activity

Andrea Menegon,¹ Dario Bonanomi,¹ Chiara Albertinazzi,¹ Francesco Lotti,^1,2 Giuliana Ferrari,^1,2 Hung-Teh Kao,³ Fabio Benfenati,⁴ Pietro Baldelli,⁴ and Flavia Valtorta^1,5

¹San Raffaele Scientific Institute and "Vita-Salute" University, 20132 Milan, Italy, ²Telethon Institute for Gene Therapy, 20132 Milan, Italy, ³Nathan Kline Institute for Psychiatric Research, Orangeburg, New York 12229, ⁴Department of Neuroscience, The Italian Institute of Technology Central Laboratories and Department of Experimental Medicine, Section of Physiology, University of Genova, 16126 Genova, Italy, and ⁵The Italian Institute of Technology, Research Unit of Molecular Neuroscience, 20132 Milan, Italy

Correspondence should be addressed to Flavia Valtorta, Department of Biological and Technological Research 3A3, San Raffaele Scientific Institute, via Olgettina 58, 20132 Milan, Italy. Email: valtorta.flavia{at}hsr.it

Protein kinase A (PKA) modulates several steps of synaptic transmission. However, the identification of the mediators of these effects is as yet incomplete. Synapsins are synaptic vesicle (SV)-associated phosphoproteins that represent the major presynaptic targets of PKA. We show that, in hippocampal neurons, cAMP-dependent pathways affect SV exocytosis and that this effect is primarily brought about through synapsin I phosphorylation. Phosphorylation by PKA, by promoting dissociation of synapsin I from SVs, enhances the rate of SV exocytosis on stimulation. This effect becomes relevant when neurons are challenged with sustained stimulation, because it appears to counteract synaptic depression and accelerate recovery from depression by fostering the supply of SVs from the reserve pool to the readily releasable pool. In contrast, synapsin phosphorylation appears to be dispensable for the effects of cAMP on the frequency and amplitude of spontaneous synaptic currents and on the amplitude of evoked synaptic currents. The modulation of depolarization-evoked SV exocytosis by PKA phosphorylation of synapsin I is primarily caused by calmodulin (CaM)-dependent activation of cAMP pathways rather than by direct activation of CaM kinases. These data define a hierarchical crosstalk between cAMP- and CaM-dependent cascades and point to synapsin as a major effector of PKA in the modulation of activity-dependent SV exocytosis.

Key words: knock-out mice; lentiviruses; neurotransmitter release; phosphorylation; synapse; trafficking

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Received April 27, 2006; revised Sept. 27, 2006; accepted Sept. 28, 2006.

Correspondence should be addressed to Flavia Valtorta, Department of Biological and Technological Research 3A3, San Raffaele Scientific Institute, via Olgettina 58, 20132 Milan, Italy. Email: valtorta.flavia{at}hsr.it

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