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Kiss-and-run or endocytosis: Maintaining the release of neurotransmitters
By Ruth SoRelle, MPH

Patrick Verstreken

Many neurological diseases, including psychiatric illnesses such as depression and schizophrenia, may arise from an imbalance in the release of chemicals called neurotransmitters. Understanding how these neurotransmitters are released can provide important insight into the genesis of these diseases.

Understanding the world of neurotransmitter release has occupied the time of Patrik Verstreken, a graduate student who has been working for more than four years in the laboratory of Hugo Bellen, DVM, PhD. Verstreken’s work has focused on the molecular mechanisms that govern neurotransmitter release. Neurotransmitters are released from the nerve ending through the fusion of little bubble-like structures called synaptic vesicles with the plasma membrane of the nerve terminal. During intense neuronal activity, (when people are thinking hard), neurons release a massive amount of transmitters and new vesicles need to be reformed at the nerve ending itself to allow the neuron to fire repetitively.

Verstreken’s work has drawn him into a controversy as to whether neurotransmitter release is maintained by endocytosis, in which new vesicles invaginate from the membrane of the nerve terminal, or whether release is maintained by a much quicker process called ‘kiss-and-run.’

Endocytosis has long been thought to be the major form of synaptic vesicle regeneration. As Verstreken describes it, “In regular exo- and endocytosis, the vesicles go to the cell membrane and fuse in response to a stimulus. They release their contents, and collapse into the membrane of the nerve terminal. Eventually, they are pulled back into the nerve ending and are refilled with transmitter.

“This has been studied for a very long time and is very well established,” said Verstreken. Several groups, including Bellen’s group, have identified the molecular requirements for this process, and it was thought that endocytosis is the main form of synaptic vesicle refilling at the nerve ending.

Kiss-and-run is a quicker process in which the vesicle fuses to the plasma membrane, but does not collapse into the membrane. Instead it is pinched off right away and then recycled on the spot. The process has been postulated for a long time, but the data supporting it were not strong, said Verstreken.

Proving that ‘kiss-and-run’ exists has been the focus of Verstreken’s work for the past two years. To produce the needed data, he has depended on the fruit fly Drosophila, one of the most powerful genetic model systems available. Almost all the genes required for neurotransmitter release and endocytosis found in vertebrate animals such as mice or men have a twin in the fruit fly.

“That makes it a very good model system in which to study these phenomena,” said Verstreken.

"Some people at first said that ‘kiss-and-run’ would happen during high rates of neuron (or nerve cell) activity," he said. However, his and others’ data now show that ‘kiss-and-run’ is actually the most prevalent form of neurotransmitter release and occurs during low levels of nerve stimulation. When nerve stimulation occurs at a high rate, endocytosis goes on as well, increasing the levels of vesicle reformation and allowing the neuron to maintain a high rate of neurotransmitter release

"Kiss-and-run is much more efficient than endocytosis," he said. To prove this, he bred flies that lack a protein called endophilin, important in the endocytosis process. Without endophilin, the synaptic vesicles cannot reform through invagination from the membrane of the nerve ending. However, Verstreken and his colleagues showed that the flies lacking endophilin have a small pool of vesicles that continue to release neurotransmitter, maintaining it at 15 to 20 percent of normal during repeated stimulation and 100 percent during milder stimulation. Because endocytosis is completely blocked, he and his colleagues determined these synaptic vesicles are carrying out ‘kiss-and-run.’

The notion of ‘kiss-and-run’ will continue to be controversial, he said. It is not the only mechanism of neurotransmitter release, but it is an important one.

Others who participated in this work published in Cell, include: Drs. Ole Kjaerulff, Thomas E. Lloyd, Richard Atkinson, Yi Zhou, and Bellen, all of Baylor, and Dr. Ian A. Meinertzhagen of the Neuroscience Center at Dalhousie University in Halifax, Nova Scotia.

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