Ca2+-dependent release of synaptotagmin-1 from the SNARE complex on phosphatidylinositol 4,5-bisphosphate-containing membranes.

Inside the brain, cells called neurons relay messages from one place to another in the form of electrical signals. When an electrical signal reaches a junction between two neurons (known as a synapse) it triggers small particles called calcium ions to enter one of the cells. This influx of calcium causes vesicles to fuse with the membrane surrounding the neuron and release molecules called neurotransmitters into the small gap between the two neurons. These molecules travel across the gap to activate an electrical signal in the second neuron which then carries the message onwards. A protein known as synaptotagmin-1 senses calcium ions at synapses and works together with a group of proteins known as the SNARE complex to help vesicles fuse with the cell membrane. Previous studies have reported three different structures of synaptotagmin-1 bound to the SNARE complex in a different way. But it was unclear which of these binding states actually result in the release of neurotransmitters. To address this question, Voleti, Jaczynska and Rizo studied how and when synptotagmin-1 and the SNARE complex bind together using two approaches known as NMR spectroscopy and fluorescence spectroscopy. The experiments suggest that before calcium enters the synapse, synaptotagmin-1 is already bound to a surface on the SNARE complex. This binding inhibits the release of neurotransmitters and has been reported in previous studies. Adding calcium ions causes synaptotagmin-1 to be released from the SNARE complex. This allows synaptotagmin-1 to interact with the membrane and cooperate with the SNARE complex to trigger vesicle fusion. Finding out how neurons release neurotransmitters at synapses may help us to understand how the brain works. This could provide new insights into how defects in the synapse lead to neurological disorders, such as schizophrenia, and potentially aid the development of new treatments for such conditions.