Lorne special: Dynamic dynamin and synaptic transmission

Phil Robinson

This feature appeared in the January/February 2010 issue of Australian Life Scientist. To subscribe to the magazine, go here.

Some astronomers have a favourite nebula. Some chemists have a favourite molecule. Professor Phil Robinson, of the Children’s Medical Research Institute in Sydney, has a favourite protein: the small GTPase, dynamin-1. And it’s this protein that will be the focus of his talk at the Lorne Conference on Protein Structure and Function in February.

Dynamin-1 is one of a whole family of dynamins that all play the same role in controlling cell internalisation by endocytosis. Dynamin-1 is a bit special in that it controls the endocytosis of synaptic vesicles in nerve cells and, therefore, the transport of neural transmitters and other goodies that make your nerve cells fire. So, if this pivotal protein does not do its thing properly or in a timely manner, the neurons tends to get a bit tired out and not work very well in regard to synaptic transmission. Robinson has been working on dynamin for a very long time now, since his postgraduate days in fact. “And one thing we showed years ago is that dynamin-1 function or activity in neurons is controlled by phosphorylation and dephosphorylation.” This process is the attaching and detaching of phosphate groups on proteins by kinase and phosphatase enzymes, respectively. This simple phosphate-state change is key to the proper functioning of many proteins and systems in biology, including synaptic vesicle endocytosis.

A strong focus of Robinson’s work has been the signalling systems that control dynamin-1 phosphorylation and dephosphorylation because the same signalling is controlling the endocytosis of synaptic vesicles.

“At the start of the project I will talk about at Lorne, we were using mass spectrometry and lots of other tools to find all of the sites of phosphorylation in dynamin. Then we ranked those sites in terms of amount of phosphate added, which responds the most when a neuron is stimulated,” Robinson explains. “There turned out to be seven, and the two that we were most interested in are at amino acid positions 774 and 778.”

The group showed some time ago that these two interesting sites are phosphorylated between nerve cell stimuli, so when a nerve is at rest it phosphorylates dynamin on sites 774 and 778. Then, when the neuron is depolarised, within one second a phosphatase called calcineurin is activated and it dephosphorylates those same two sites. However, what is new and different about Robinsons’s findings earlier this year is that the phosphatase that turns on dynamin is calcineurin.

“So, a calcium-dependent phosphatase depolarises the neuron to activate synaptic transmission, which causes calcium influx that turns on synaptic transmission and activates calcineurin, which then dephosphorylates dynamin, thus, endocytosis is turned on.”

The readout for all of this is rates of synaptic vesicle endocytosis (SVE), which measures all the processes including exocytosis that go together for synaptic transmission in the neuron, i.e. one nerve firing onto another.

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