When an action potential reaches the presynaptic terminal, it triggers the release of neurotransmitters into the synaptic cleft. This process involves the opening of voltage-gated calcium channels, calcium-dependent activation of synaptic proteins, and fusion of synaptic vesicles with the terminal membrane. These events ensure precise and rapid communication between neurons.

Action Potential

As we have covered, when an action potential propagates down the axon to the presynaptic terminal, the electrical signal will result in a release of chemical neurotransmitters that will communicate with the postsynaptic cell.

Animation 10.1. The action potential is a brief change in electrical potential across the membrane. Starting at the axon hillock, the membrane potential shifts from a resting value of -65 mV to a positive value and back to rest as the signal propagates down the axon. When the action potential reaches the presynaptic terminal, it triggers the release of chemical neurotransmitter. ‘Action Potential Propagation’ by Casey L. Henley (CC-BY-NC-SA). View detailed alternative text.

Ion flow in Terminal

Calcium influx is the step that converts the electrical action potential into a chemical signal

When the action potential reaches the terminal, there is an influx of sodium ions, just like when the action potential moves down the axon. This inward current causes a depolarization of the terminal, and that depolarization activates voltage-gated calcium channels. There is a strong electrochemical gradient that moves calcium into the terminal.

Animation 10.2. Terminal calcium influx. Action potential arrival causes sodium influx (through blue dotted voltage-gated sodium channels), depolarizing the terminal membrane. This depolarization opens voltage-gated calcium channels (purple striped), allowing calcium to flow into the terminal down its strong electrochemical gradient, triggering neurotransmitter release. ‘Terminal Calcium Influx’ by Casey L. Henley (CC-BY-NC-SA). View detailed alternative text.

Active Zones

The voltage-gated calcium channels are concentrated in the presynaptic terminal at active zones, the regions of the membrane where small molecule neurotransmitters are released. At active zones, some synaptic vesicles are docked and are ready for immediate release upon arrival of the action potential. Other neurotransmitter-filled vesicles remain in a reserve pool outside of the active zone.

Vesicles filled with neuropeptides do not dock at active zones. They are located outside of the active zone, further away from the membrane and the high density of voltage-gated calcium channels and are therefore slower to release than the small molecule transmitters.

Vesicle Docking

Docking of synaptic vesicles packaged with small molecule neurotransmitters occurs through the interaction of three membrane-bound proteins called SNARE proteins. Synaptobrevin is called a v-SNARE because it is located on the Vesicular membrane. Syntaxin and SNAP-25 are called t-SNARES because they are located on the terminal membrane, which is the Target membrane. The interaction of these three proteins leads to vesicle docking at the active zone.

Exocytosis

Because exocytosis requires calcium binding, release stays tightly linked to action potential timing

The influx of calcium through the voltage-gated calcium channels initiates the exocytosis process that leads to neurotransmitter release. Calcium enters the cell and interacts with another vesicle-bound protein called synaptotagmin. This protein is a calcium sensor, and when calcium is present at the active zone, synaptotagmin interacts with the SNARE proteins. This is the first step toward exocytosis of the synaptic vesicle.

Animation 10.3. Synaptotagmin as calcium sensor. When voltage-gated calcium channels (purple striped) open, calcium enters the terminal and binds to synaptotagmin in the vesicle membrane. This triggers synaptotagmin to interact with SNARE proteins, initiating the exocytosis cascade. ‘Synaptotagmin’ by Casey L. Henley (CC-BY-NC-SA). View detailed alternative text.

Once synaptotagmin interacts with the SNARE proteins, the synaptic vesicle membrane fuses with the presynaptic terminal membrane, exocytosis occurs, and the neurotransmitters are released.

Animation 10.4. Transmitter exocytosis. After synaptotagmin binds calcium and interacts with SNARE proteins, the vesicle and terminal membranes fuse, forming a pore that releases neurotransmitters into the synaptic cleft. ‘Transmitter Exocytosis’ by Casey L. Henley (CC-BY-NC-SA). View detailed alternative text.

Neurotransmitter Action

After exocytosis of the transmitter molecules, they enter the synaptic cleft and bind to receptors on the postsynaptic membrane. Receptors fall into two main categories: ligand-gated channels and G-protein coupled receptors. The next two chapters cover these receptors.

Conclusion

The release of neurotransmitters is a highly coordinated process involving electrical, chemical, and molecular mechanisms. From calcium influx to vesicle fusion, each step ensures efficient signal transmission, laying the foundation for complex neural communication.

Video Lecture