Protein kinase A-mediated synapsin I phosphorylation is a central modulator of Ca2+-dependent synaptic activity

Andrea Menegon, Dario Bonanomi, Chiara Albertinazzi, Francesco Lotti, Giuliana Ferrari, Hung Teh Kao, Fabio Benfenati, Pietro Baldelli, Flavia Valtorta

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)11670-11681
Number of pages12
JournalJournal of Neuroscience
Volume26
Issue number45
DOIs
Publication statusPublished - Nov 8 2006

Keywords

  • Knock-out mice
  • Lentiviruses
  • Neurotransmitter release
  • Phosphorylation
  • Synapse
  • Trafficking

ASJC Scopus subject areas

  • Neuroscience(all)

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