Neurotransmitter Release: Vesicles, Calcium and SNAREs

The molecular machinery of the presynaptic terminal: quantal release, calcium triggering, the SNARE proteins that zip vesicles to the membrane, and the toxins — botulinum and tetanus — that cut them.

Chemical transmission must be both fast and precise: transmitter is released within a fraction of a millisecond after an action potential arrives. The machinery behind that is one of the best-understood molecular systems in biology.

Release comes in packets

In the early 1950s Bernard Katz and colleagues, recording from frog nerve-muscle junctions, noticed small spontaneous blips in the muscle's voltage, all roughly the same size. Larger responses were whole multiples of them. They proposed that transmitter is released in fixed quanta — packets — later identified as the contents of single synaptic vesicles. Katz shared the 1970 Nobel Prize.

Docking, priming and fusion

Vesicles are filled by transporter pumps, then docked at specialised release sites, the active zones, and primed for release. The key proteins are the SNAREs: synaptobrevin on the vesicle, and syntaxin and SNAP-25 on the plasma membrane. They twist together into a tight four-helix bundle, pulling the two membranes so close that they fuse. The vesicle's contents spill into the cleft.

The calcium trigger

Fusion waits for a signal. When an action potential opens voltage-gated calcium channels clustered right beside the active zone, calcium concentration rises locally by a thousand-fold or more within microseconds. The calcium sensor synaptotagmin binds it and triggers the half-zipped SNAREs to complete fusion. James Rothman, Randy Schekman and Thomas Südhof shared the 2013 Nobel Prize for discovering this vesicle-trafficking machinery.

Recycling

After fusion, vesicle membrane is retrieved by endocytosis, refilled and reused — a cycle that can repeat many times a minute at an active synapse.

Toxins that cut the zipper

Botulinum toxin, among the most potent poisons known, and tetanus toxin are enzymes that cut specific SNARE proteins. Botulinum acts at nerve-muscle junctions, blocking acetylcholine release and causing paralysis. In tiny, controlled doses — Botox — it relaxes wrinkles, treats certain muscle spasms and is approved for preventing chronic migraine.