Calcium Assists Dopamine Release by Preventing Aggregation on the Inner Leaflet of Presynaptic Vesicles

In
this study, the dopamine–lipid bilayer interactions were probed
with three physiologically relevant ion compositions using atomistic
molecular dynamics simulations and free energy calculations. The in
silico results indicate that calcium is able to decrease significantly
the binding of dopamine to a neutral (zwitterionic) phosphatidylcholine
lipid bilayer model mimicking the inner leaflet of a presynaptic vesicle.
We argue that the observed calcium-induced effect is likely in crucial
role in the neurotransmitter release from the presynaptic vesicles
docked in the active zone of nerve terminals. The inner leaflets of
presynaptic vesicles, which are responsible for releasing neurotransmitters
into the synaptic cleft, are mainly composed of neutral lipids such
as phosphatidylcholine and phosphatidylethanolamine. The neutrality
of the lipid head group region, enhanced by a low pH level, should
limit membrane aggregation of transmitters. In addition, the simulations
suggest that the high calcium levels inside presynaptic vesicles prevent
even the most lipophilic transmitters such as dopamine from adhering
to the inner leaflet surface, thus rendering unhindered neurotransmitter
release feasible.