A, Major ion conductances are triggered by an action potential (AP). B, Their effects on neurotransmitter (NT) release as related to ligand-gated channels influencing postsynaptic excitability. NT is packaged in synaptic vesicles; these vesicles, in response to nerve terminal depolarization and Ca+2 influx, merge with the nerve terminal membrane through a mechanism involving the SNARE complex.Through this mechanism of docking proteins, membrane fusion, and NT exocytosis, multiple vesicles simultaneously release their NT content, called quantal release, allowing postsynaptic stimulation. SNARE proteins represent a large superfamily of soluble NSF (N-ethylmaleimide-sensitive factor) attachment protein receptors that are composed of four alpha helices that mediate vesicle fusion and exocytosis. C, Metabotropic receptors responding to nerve terminal depolarization with SNARE complex-mediated vesicle membrane fusion and exocytosis. Both postsynaptic and presynaptic receptors bind with NT (in this case norepinephrine, NE) and transduce the receptor-ligand binding into intracellular signaling. The presynaptic receptor can modulate nerve terminal excitability and subsequent NT release. The postsynaptic receptor can modulate postsynaptic excitability and the postsynaptic membrane responsiveness to other NTs. High-affinity uptake carriers remove NE from the synaptic cleft back into the nerve terminal for repackaging into synaptic vesicles. This NE uptake carrier also can take up epinephrine (E) from the circulation. Uptaken E also is repackaged into the NE synaptic vesicles and is preferentially released on subsequent nerve terminal depolarization. This E substitute-NT mechanism provides augmented receptor activation (especially beta receptor activation by E) during sympathetic responses.
Botulinum toxin (BOTOX) is a proteolytic enzyme that cleaves SNARE proteins in nerve terminals, preventing vesicle fusion with the nerve terminal membrane and release of NT. Hence, nerve APs do not result in NT release; for muscles targeted by cholinergic motor end plates, botulinum toxin results in muscle paralysis. Deliberate clinical use of this toxin can alleviate muscle spasm in spasmodic torticollis, dystonia, and other conditions of excess chronic muscle contraction. This toxin is also used cosmetically to reduce or eliminate the appearance of facial skin wrinkles through selective paralysis of facial muscles.