Protein Key To Trafficking In Nerve Terminals

Identifying this protein - Dap160 — and its function is an important step in understanding how neurons communicate with one another, said Dr. Hugo Bellen, BCM professor of molecular and human genetics, a Howard Hughes Medical Institute investigator, and director of the program in developmental biology. The report appears in the July 22, 2004, issue of the journal Neuron.

Dap 160 was found as part of a new screen developed in Bellen's laboratory. The screen revealed many genes involved in neuronal function and development, said Bellen. Dap160 stands for Dynamin-associated protein of 160 kD (kilodaltons). Dynamin is a protein that is crucial to the final portion of the synaptic process.

Neurotransmitters are the chemicals that contain the message to be transmitted when neurons talk to each other or to other cells. These chemicals are contained in small vesicles inside nerve endings called synapses.

When a nerve pulse invades the nerve ending, these vesicles fuse with the membrane at the tip of the nerve ending (called the synaptic membrane). At this point, vesicles release their contents so that a nearby cell receives the message.

"You need to retrieve the vesicles at the synapse to maintain a constant supply of vesicles in the nerve terminal," said Bellen. At least two distinct types of vesicle retrieval occur at the synapse, but the most well studied mechanism of vesicle retrieval is based on retrieving little pieces of membrane from the synaptic membrane. As the vesicles start to bud off the cell membrane, dynamin accumulates on the vesicle. The role of this protein is still controversial, Bellen said. Some people think it's a "pinchase," pinching the vesicle off the cell membrane. Others think that it recruits other proteins to help pinching off the vesicle.

When Dap160, which binds dynamin, is removed from the vesicle retrieval process, the pinching-off either does not occur properly, or occurs too late. As a result, the vesicle keeps growing and subsequently becomes loaded with too much neurotransmitter. Bellen and his colleagues believe that Dap160 stabilizes the complex of molecules involved in the retrieval and formation of vesicles, allowing for neurotransmitters to be released in a continuous fashion.

"Besides budding from the membrane, there is at least one other form of vesicle retrieval at the synapse", Bellen said. A rapid retrieval mechanism called "kiss and run" occurs when the vesicle fuses with the membrane but the vesicle membrane does not collapse into the synaptic membrane. Rather, kiss and run vesicles release neurotransmitters through a pore in the membrane. The vesicles are then retrieved by pinching of the fusion pore at the site of release. These vesicles stay close to release sites and are reused immediately.

Interestingly, Dap160 is not only involved in retrieving vesicles from the membrane, but it is also implicated in kiss and run type vesicle recycling. This has important implications for the regulation of vesicle retrieval mechanisms at the synapse, Bellen said.

The main authors of the study are Tong-Wey Koh and Patrik Verstreken, both associated with BCM.