NEUROTRANSMITTER
RELEASE
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.
CLINICAL POINT
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.
