Biomedical Engineering Reference
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from the cell. Due to its long half-life, residual Ca
2+
can easily build up by temporal
and spatial summation during high-frequency repetitive activity to reach levels in
the low
M range.
Due to the kinetics of Ca
2+
transients, two not mutually exclusive mechanisms
can account for the synchronous and asynchronous components of release, namely:
(1) an “allosteric model” based on a different Ca
2+
sensitivity of the two processes,
but with a homogeneous machinery and (2) the “two-Ca
2+
sensor model,” based on
selective genetic deletions of Ca
2+
sensors, holding that different sensors present in
distinct SV pools or coexisting in the same SVs mediate the two forms of release: a
low-affinity sensor with fast on/off rates that sustains fast synchronous release and a
high-affinity sensor with slow off rate that is involved in sustaining asynchronous
release (Kochubey et al.
2011
; Walter et al.
2011
). According to this view, a
countinuum
of Ca
2+
concentration levels would direct the spectrum of the release
modes. While synchronous release requires high concentrations (10-50
ʼ
M) at the
channel nanodomains with very fast dynamics and strong cooperativity, spatially
averaged/slow decaying residual Ca
2+
buildup following high-frequency activity
and/or release from intracellular stores triggers asynchronous release, characterized
by linear dependence on the Ca
2+
concentration. Even lower basal Ca
2+
concen-
trations facilitate spontaneous release. Notably, the same mechanisms triggering
asynchronous release also promote the expression of short-term plasticity.
Synchronous release has been so far intensely connected with members of the
synaptotagmin (Syt) family of SV Ca
2+
sensors. Out of 16 isoforms of
synaptotagmin that were identified, only Syt 1-9 bind Ca
2+
through specific Ca
2+
/
phospholipid binding domains (C2 domains; Pang and S¨dhof
2010
). Among the
latter group, Syt-1, Syt-2, and Syt-9 are considered fast sensors mediating synchro-
nous release. Deletions of Syt-1, Syt-2, or of the SNARE complex-associated
protein complexin lead to a complete loss of synchronous release at both excitatory
and inhibitory synapses, while asynchronous release is preserved and even
enhanced at high stimulation frequencies. The knockdown of Syt-7 at the zebrafish
neuromuscular junction reduces asynchronous release; however, it has no effect on
synchronous/asynchronous release in central synapses.
The mechanisms behind asynchronous release are still far from being under-
stood, but recent work has proposed several hypotheses. One potential mechanism
involves a distinct slow presynaptic Ca
2+
sensor, Doc2, that binds Ca
2+
with slower
kinetics, and its knockdown in hippocampal cultures results in reduced asynchro-
nous release (Yao et al.
2011
). Another recent report proposes that the SNARE
protein VAMP2 drives synchronous release, while its isoform VAMP4 boosts
asynchronous release. Moreover, it was also recently shown that both voltage-
gated presynaptic Cav-2.1 and Cav-2.2 channels that conduct P/Q-type and
N-type Ca
2+
currents, respectively, are characterized by a prolonged Ca
2+
current
that promotes asynchronous release (Few et al.
2012
). In this respect, we have
recently shown that the SV phosphoprotein synapsin II constitutively enhances
asynchronous GABA release by specifically interacting with the P/Q-type channel,
while its isoform synapsin I has the opposite effect and boosts synchronous GABA
release (Medrihan et al.
2013
). Although most studies agree that the synchronous
ʼ
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