The function of dynamin phosphorylation sites in synaptic vesicle endocytosis

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Neurons communicate with each other via the release of neurotransmitters which are packaged in synaptic vesicles inside nerve endings. There are a finite number of vesicles, so they are recycled (endocytosis) for reuse. Synaptic vesicle exocytosis is very fast and normally endocytosis is a little slower, mopping up the used vesicles. Recently we showed that endocytosis can control synaptic transmission, hence it's an integral part of an overall cycle of synaptic transmission. We found that when endocytosis cannot keep up then exocytosis slows, greatly reducing the function of neurons. A complete block would result in paralysis of brain and muscles. Our team has been revealing the underlying molecular mechanisms of endocytosis in order to better understand diseases of the synapse like schizophrenia, epilepsy and Alzheimer's disease. We discovered that endocytosis is a regulated process at the heart of which is a pair of phosphorylation sites (points of phosphate attachment) in the key protein dynamin I. Our hypothesis is that endocytosis occurs in two forms, fast and slow. We propose to test the idea that proteins that associate with dynamin via the phosphorylation sites determine whether the fast or slow mode is used. Additionally, we propose that the first phosphorylation site is the trigger for endocytosis, while the second serves to recruit reserve supplies of dynamin to support the slow mode when it's required. A better understanding of Dyn and endocytosis is crucial to understanding brain disorders of synaptic transmission and ultimately for developing therapies. For example, a seizure is the uncontrolled firing of neurons. Our overall aim is to understand the control mechanisms of nerve communication to ultimately allow us to treat disorders of nerve communication like epilepsy.