Trends in Neurosciences
ReviewThe dephosphins: dephosphorylation by calcineurin triggers synaptic vesicle endocytosis
Section snippets
The dephosphins
The dephosphins are nerve terminal proteins that have little structural relationship, but are grouped together by two criteria: (1) they are essential for SV endocytosis (SVE); and (2) they are rapidly and coordinately dephosphorylated in nerve terminals after activation of Ca2+ influx through voltage-dependent Ca2+ channels. This dephosphorylation is mediated by a single enzyme, the Ca2+–calmodulin-dependent phosphatase, calcineurin (CaN). Seven dephosphins have been identified to date. The
The dephosphins are essential for SVE
Most dephosphins were found to be essential for SVE before their identification as CaN substrates. They act sequentially at stages that fall into four distinct categories: nucleation, invagination, fission and uncoating (Fig. 2).
The phosphorylation cycle of the dephosphins controls SVE
Although each dephosphin has an essential role(s) at overlapping stages of the endocytosis pathway, is their phosphorylation status essential for SVE? The link has been shown to be strong in research involving isolated brain nerve terminals (synaptosomes). First, every CaN substrate identified to date in synaptosomes is essential for SVE in its dephosphorylated form. Second, recent studies have shown that CaN-mediated dephosphorylation triggers SVE, and the rephosphorylation of various
How does protein phosphorylation regulate SVE?
How does the dephosphorylation–phosphorylation cycle of the dephosphins allow them to control SVE? The dephosphins share characteristics that could be important: (1) common interactions with nerve terminal proteins that are essential for endocytosis (Fig. 1, Fig. 2); and (2) their recruitment or translocation to the plasma membrane during endocytosis and their subsequent release into the cytosol (Fig. 3). Recent in vitro evidence suggests both of these factors might play a role, with the
Concluding remarks and perspectives
It is clear that dephosphorylation–phosphorylation of the dephosphins is of crucial importance to SVE, with dephosphorylation stimulating the process, and phosphorylation acting as a potent inhibitor. Can we now understand why the dephosphins are the only known example in biology of the coordinated dephosphorylation of a large group of diverse proteins, each sharing roles in the same biological response? The concepts discussed provide a framework for how the dephosphins possibly control SVE.
Acknowledgements
The authors’ research was supported by The National Health and Medical Research Council of Australia.
References (65)
Phosphorylation of dynamin I and synaptic vesicle recycling
Trends Neurosci.
(1994)Amphiphysin I is associated with coated endocytic intermediates and undergoes stimulation-dependent dephosphorylation in nerve terminals
J. Biol. Chem.
(1997)Identification and characterization of a nerve terminal-enriched amphiphysin isoform
J. Biol. Chem.
(1997)A new member of the amphiphysin family connecting endocytosis and signal transduction pathways
J. Biol. Chem.
(1997)p145, a major Grb2-binding protein in brain, is co-localized with dynamin in nerve terminals where it undergoes activity-dependent dephosphorylation
J. Biol. Chem.
(1994)The interaction of epsin and eps15 with the clathrin adaptor AP-2 is inhibited by mitotic phosphorylation and enhanced by stimulation-dependent dephosphorylation in nerve terminals
J. Biol. Chem.
(1999)Dissociation between Ca2+-triggered synaptic vesicle exocytosis and clathrin-mediated endocytosis at a central synapse
Neuron
(1998)- et al.
The endocytic machinery in nerve terminals surrounds sites of exocytosis
Curr. Biol.
(1999) Synaptic vesicle size and number are regulated by a clathrin adaptor protein required for endocytosis
Neuron
(1998)Eps15 is a component of clathrin-coated pits and vesicles and is located at the rim of coated pits
J. Biol. Chem.
(1996)
Assembly of clathrin coats disrupts the association between eps15 and AP-2 adaptors
J. Biol. Chem.
AP180 and AP-2 interact directly in a complex that cooperatively assembles clathrin
J. Biol. Chem.
Epsin binds to clathrin by associating directly with the clathrin-terminal domain. Evidence for cooperative binding through two discrete sites
J. Biol. Chem.
Mapping of eps15 domains involved in its targeting to clathrin-coated pits
J. Biol. Chem.
Calcium triggers calcineurin-dependent synaptic vesicle recycling in mammalian nerve terminals
Curr. Biol.
The N-terminus of amphiphysin II mediates dimerization and plasma membrane targeting
J. Biol. Chem.
Endophilin/SH3p4 is required for the transition from early to late stages in clathrin-mediated synaptic vesicle endocytosis
Neuron
Fission and uncoating of synaptic clathrin-coated vesicles are perturbed by disruption of interactions with the SH3 domain of endophilin
Neuron
Dynamin undergoes a GTP-dependent conformational change causing vesiculation
Cell
Essential role of phosphoinositide metabolism in synaptic vesicle recycling
Cell
The calcineurin binding protein Cain is a negative regulator of synaptic vesicle endocytosis
J. Biol. Chem.
The calcineurin–dynamin 1 complex as a calcium sensor for synaptic vesicle endocytosis
J. Biol. Chem.
Cain, a novel physiologic protein inhibitor of calcineurin
J. Biol. Chem.
Calmodulin is the divalent cation receptor for rapid endocytosis, but not exocytosis, in adrenal chromaffin cells
Neuron
An inhibitory role of calcineurin in endocytosis of synaptic vesicles at nerve terminals of Drosophila larvae
Neurosci. Res.
Phosphorylation of dynamin I on Ser-795 by protein kinase C blocks its association with phospholipids
J. Biol. Chem.
Phosphorylation of dynamin by ERK2 inhibits the dynamin-microtubule interaction
FEBS Lett.
Amphiphysin binds the cdk5 regulatory subunit p35 and is phosphorylated by cdk5 and cdc2
J. Biol. Chem.
Regulation of complex formation of POB1/epsin/adaptor protein complex 2 by mitotic phosphorylation
J. Biol. Chem.
Phosphorylation, high ionic strength, and calmodulin reverse the binding of MARCKS to phospholipid vesicles
J. Biol. Chem.
A phospho-switch controls the dynamic association of synapsins with synaptic vesicles
Neuron
Dynamin I is a Ca2+-sensitive phospholipid-binding protein with very high affinity for protein kinase C
J. Biol. Chem.
Cited by (286)
Protein phosphorylation in depolarized synaptosomes: Dissecting primary effects of calcium from synaptic vesicle cycling
2021, Molecular and Cellular ProteomicsCitation Excerpt :As indicated above, our first quantitative analysis does not allow for differentiating phosphorylation changes that are directly dependent on active membrane trafficking in the synapse rather than being caused by the activation of calcium-dependent kinases and phosphatases such as CaMKII (23), calcineurin (86), etc. Of course, these processes are intertwined since these enzymes are known to regulate the phosphorylation status of proteins closely associated with the process of SV cycling (87, 88). We suppressed SV cycling by incubating synaptosomes with BoNT that block exocytosis by cleaving SNARE proteins.
Membrane transformations of fusion and budding
2024, Nature CommunicationsBIN1<sup>K358R</sup> suppresses glial response to plaques in mouse model of Alzheimer's disease
2024, Alzheimer's and Dementia