Trends in Neurosciences
Volume 24, Issue 11, 1 November 2001, Pages 659-665
Journal home page for Trends in Neurosciences

Review
The dephosphins: dephosphorylation by calcineurin triggers synaptic vesicle endocytosis

https://doi.org/10.1016/S0166-2236(00)01930-5Get rights and content

Abstract

When nerve terminals in the brain are stimulated, a group of phosphoproteins called the dephosphins are coordinately dephosphorylated by calcineurin, the Ca2+-dependent protein phosphatase. Amazingly, the seven presently known dephosphins are not structurally related, yet each has been independently shown to be essential for synaptic vesicle endocytosis (SVE). Nowhere else in biology is there a similar example of the coordinated dephosphorylation of such a large group of proteins each sharing roles in the same biological response. This suggests that dephosphorylation and phosphorylation of the dephosphins is essential for SVE. Recent studies in synaptosomes have confirmed this view, with calcineurin-mediated dephosphorylation of the dephosphins essential for triggering SVE. The phosphorylation cycle of the dephosphins might regulate SVE by targeting the proteins to sites of action and by stimulating the assembly of several large essential endocytic protein complexes.

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.

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