Phosphorylation by cAMP-dependent protein kinase is essential for synapsin-induced enhancement of neurotransmitter release in invertebrate neurons

Fiumara, Ferdinando; Giovedì, Silvia; Menegon, Andrea; Milanese, Chiara; Merlo, Daniela; Montarolo, Pier Giorgio; Valtorta, Flavia; Benfenati, Fabio; Ghirardi, Mirella

doi:10.1242/jcs.01388

Cited by 54 publications

(51 citation statements)

References 59 publications

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“…Synapsin suppression delays neuronal differentiation, axonal extension, and synaptogenesis Ferreira et al, 1995), whereas the precocious expression of synapsins leads to accelerated maturation of synapses formed in culture (Lu et al, 1992;Schaeffer et al, 1994;Valtorta et al, 1995;Fiumara et al, 2004). Exogenous synapsin I loaded into embryonic Xenopus spinal neurons induces profound structural rearrangements of the developing neuromuscular synapses, including the precocious compartmentalization of SVs in nerve terminals, accompanied by the early appearance of a mature form of quantal secretion (Lu et al, 1992;Valtorta et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of Synapsin I by cAMP-Dependent Protein Kinase Controls Synaptic Vesicle Dynamics in Developing Neurons

Bonanomi¹,

Menegon²,

Miccio³

et al. 2005

J. Neurosci.

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In developing neurons, synaptic vesicles (SVs) undergo cycles of exo-endocytosis along isolated axons. However, it is currently unknown whether SV exocytosis is regulated before synaptogenesis. Here, we show that cAMP-dependent pathways affect SV distribution and recycling in the axonal growth cone and that these effects are mediated by the SV-associated phosphoprotein synapsin I. The presence of synapsin I on SVs is necessary for the correct localization of the vesicles in the central portion of the growth cone. Phosphorylation of synapsin I by cAMP-dependent protein kinase (protein kinase A) causes the dissociation of the protein from the SV membrane, allowing diffusion of the vesicles to the periphery of the growth cone and enhancing their rate of recycling. These results provide new clues as to the bases of the well known activity of synapsin I in synapse maturation and indicate that molecular mechanisms similar to those operating at mature nerve terminals are active in developing neurons to regulate the SV life cycle before synaptogenesis.

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Section: Discussionmentioning

confidence: 99%

Phosphorylation of Synapsin I by cAMP-Dependent Protein Kinase Controls Synaptic Vesicle Dynamics in Developing Neurons

Bonanomi¹,

Menegon²,

Miccio³

et al. 2005

J. Neurosci.

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“…Because synapsins have been described to promote synaptic maturation in a PKA-dependent manner (Fiumara et al, 2004) and mediate SV clustering at the synaptic terminal , we ascertained that, under our conditions, the density of synaptic contacts and/or the number of SVs present in the terminals (indirectly evaluated by measuring the levels of synaptophysin I immunoreactivity) were unchanged by expression of exogenous synapsin I in synapsin I knock-out neurons (supplemental Fig. 1C, available at www.jneurosci.org as supplemental material).…”

Section: Synapsin Phosphorylation and Sv Recycling Are Closely Correlmentioning

confidence: 99%

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

Menegon¹,

Bonanomi²,

et al. 2006

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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.

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“…Extensive analysis of the phosphorylation of exocytotic proteins has yielded many substrates of PKA such as synapsin (Fiumara et al, 2004), cysteine string protein (Evans and Morgan, 2003), syntaphilin (Boczan et al, 2004), SNAP-25 (Nagy et al, 2004), and Snapin (Thakur et al, 2004). However, physiological effects attributed to their phosphorylation as well as exact molecular mechanisms still remain unexplained.…”

Section: Discussionmentioning

confidence: 99%

Protein kinase A-dependent phosphorylation of B/K protein

Chin

Choi²,

Jang³

et al. 2006

Exp Mol Med

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We have previously isolated a novel protein "B/K" that contains two C2-like domains. Here, we report the isolatioin and mRNA distribution of a human B/K isoform, and protein kinase A (PKA)-dependent phosphorylation of the B/K protein. The 1.5 kb human B/K cDNA clone exhibits 89% and 97% identities with rat B/K in the sequences of nucleotide and amino acid, respectively. Human B/K isoform encodes a 474 amino acid protein and shows structural features similar to the rat counterpart including two C2 domains, three consensus sequences for PKA, absence of a transmembrane region, and conservation of the N-terminal cysteine cluster. On Northern and dot blot analyses, a 3.0 kb B/K transcript was abundantly present in human brain, kidney, and prostate. Among the brain regions, strong signals were observed in the frontal and temporal lobes, the hippocampus, the hypothalamus, the amygdala, the substantia nigra, and the pituitary. Recombinant B/K proteins containing three consensus sites for PKA was very efficiently phosphorylated in vitro by PKA catalytic subunit. B/K protein which was overexpressed in LLC-PK1 cells was also strongly phosphorylated in vivo by vasopressin analog DDAVP, and PKA-specific inhibitor H89 as well as type 2 vasopressin receptor antagonist specifically suppressed DDAVP-induced B/K phosphorylation. These results suggest that B/K proteins play a role as potential substrates for PKA in the area where they are expressed.

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Phosphorylation by cAMP-dependent protein kinase is essential for synapsin-induced enhancement of neurotransmitter release in invertebrate neurons

Abstract: synapsin I with phospholipids, possible role in synaptic vesicle clustering and in the maintenance of bilayer structures.

Cited by 54 publications

References 59 publications

Phosphorylation of Synapsin I by cAMP-Dependent Protein Kinase Controls Synaptic Vesicle Dynamics in Developing Neurons

Phosphorylation of Synapsin I by cAMP-Dependent Protein Kinase Controls Synaptic Vesicle Dynamics in Developing Neurons

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

Protein kinase A-dependent phosphorylation of B/K protein

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Phosphorylation by cAMP-dependent protein kinase is essential for synapsin-induced enhancement of neurotransmitter release in invertebrate neurons

Abstract: synapsin I with phospholipids, possible role in synaptic vesicle clustering and in the maintenance of bilayer structures.

Cited by 54 publications

References 59 publications

Phosphorylation of Synapsin I by cAMP-Dependent Protein Kinase Controls Synaptic Vesicle Dynamics in Developing Neurons

Phosphorylation of Synapsin I by cAMP-Dependent Protein Kinase Controls Synaptic Vesicle Dynamics in Developing Neurons

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

Protein kinase A-dependent phosphorylation of B/K protein

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