Dynamin

Can we control nerve communication to ultimately allow us to treat disorders of nerve communication?  Blocking the endocytosis step in synaptic vesicle recycling quickly results in paralysis.  More subtle control of endocytosis may be very effective in treating neurological disorders.

Many years ago, we discovered that the protein dynamin plays a central role in endocytosis.  It can assemble into a tiny nanospring that can pop off empty synaptic vesicles from the cell wall back inside the neuron for recycling.  We initially discovered dynamin as a phosphoprotein that is rapidly dephosphorylated upon stimulation of nerve terminals.  We deciphered the molecular mechanisms of its phosphorylation cycle.  Calcineurin (an enzyme that removes phosphate from proteins) dephosphorylates dynamin to initiate endocytosis by forcing it to move towards sites of endocytosis.  Once endocytosis is complete, cyclin-dependent protein kinase 5 (Cdk5) phosphorylates dynamin (attaches phosphate to it) to prepare it for the next round of vesicle recycling.  We have now identified all of the specific sites of phosphorylation in dynamin.  The current focus is to work out the roles of these sites in the endocytic machinery.  To do this, we have mutated the phosphorylation sites individually and transfected the mutant dynamin back into neurons grown in culture.  This revealed that each site plays an essential role in endocytosis, and that they work co-operatively for maximal effect.  The mutants also lead to the discovery of the specific protein that is recruited to dynamin when it is dephosphorylated.  Thus we have discovered dynamin's protein partner for endocytosis in neurons.  This understanding will ultimately help us design new strategies to approach brain disorders.