Presynaptic neurotransmitter release machinery

The presynaptic neurotransmitter release machinery is a highly coordinated assembly of proteins that mediates the fusion of synaptic vesicles with the presynaptic membrane to release neurotransmitters into the synaptic cleft. The central component is the SNARE (Soluble N-ethylmaleimide-sensitive factor Attachment protein REceptor) complex, consisting of the vesicle-associated protein VAMP-2 (synaptobrevin) and the plasma membrane proteins SNAP-25 and Syntaxin-1 (Südhof, 2013). This machinery is activated by an influx of calcium ions through voltage-gated calcium channels, which is sensed by synaptotagmin-1, leading to rapid membrane fusion (Jahn & Fasshauer, 2012). Dysfunction in these processes is linked to several neurological and psychiatric conditions, including Lambert-Eaton myasthenic syndrome, epilepsy, and schizophrenia (Waites & Garner, 2011). This machinery is the specific target of Botulinum and Tetanus neurotoxins, which act as zinc-dependent endopeptidases to cleave SNARE proteins and block neurotransmission (Pirazzini et al., 2017). Pharmacological modulation of this system, such as through the use of amifampridine to enhance calcium-dependent release or gabapentinoids to modulate calcium channel subunits, is used to treat neuromuscular and neuropathic disorders (Sanders et al., 2018).

Other names

SNARE complexSynaptic vesicle fusion machineryExocytotic apparatusPresynaptic active zoneNeurotransmitter release apparatus

Drugs and toxins targeting this machinery typically act by either proteolytically cleaving core SNARE proteins to inhibit vesicle fusion, or by modulating presynaptic calcium and potassium channels to alter the electrochemical trigger for neurotransmitter release.