Illustration showing how several synaptotagmins (yellow) work together to promote a vesicle (blue circle) to fuse with the outer membrane (blue rectangle) by binding to calcium (green circles) and PIP2 (black). Image credit: Manon Berns and Janus Kobbersmed (CC BY 4.0)
For our brains and nervous systems to work properly, the nerve cells within them must be able to ‘talk’ to each other. They do this by releasing chemical signals called neurotransmitters which other cells can detect and respond to.
Neurotransmitters are packaged in tiny membrane-bound spheres called vesicles. When a cell of the nervous system needs to send a signal to its neighbours, the vesicles fuse with the outer membrane of the cell, discharging their chemical contents for other cells to detect. The initial trigger for neurotransmitter release is a short, fast increase in the amount of calcium ions inside the signalling cell. One of the main proteins that helps regulate this process is synaptotagmin which binds to calcium and gives vesicles the signal to start unloading their chemicals.
Despite acting as a calcium sensor, synaptotagmin actually has a very low affinity for calcium ions by itself, meaning that it would not be efficient for the protein to respond alone. Synpatotagmin is more likely to bind to calcium if it is attached to a molecule called PIP2, which is found in the membranes of cells The effect also occurs in reverse, as the binding of calcium to synaptotagmin increases the protein’s affinity for PIP2. However, how these three molecules – synaptotagmin, PIP2, and calcium – work together to achieve the physiological release of neurotransmitters is poorly understood.
To help answer this question, Kobbersmed, Berns et al. set up a computer simulation of ‘virtual vesicles’ using available experimental data on synaptotagmin’s affinity with calcium and PIP2. In this simulation, synaptotagmin could only trigger the release of neurotransmitters when bound to both calcium and PIP2. The model also showed that each ‘complex’ of synaptotagmin/calcium/PIP2 made the vesicles more likely to fuse with the outer membrane of the cell – to the extent that only a handful of synaptotagmin molecules were needed to start neurotransmitter release from a single vesicle.
These results shed new light on a biological process central to the way nerve cells communicate with each other. In the future, Kobbersmed, Berns et al. hope that this insight will help us to understand the cause of diseases where communication in the nervous system is impaired.
