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J Neurosci. 2014 Sep 17;34(38):12622-35. doi: 10.1523/JNEUROSCI.1990-14.2014.

An alien divalent ion reveals a major role for Ca²⁺ buffering in controlling slow transmitter release.

Author information

1
Laboratory of Synaptic Mechanisms, Brain Mind Institute, School of Life Science, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland, and.
2
Blue Brain Project, Brain Mind Institute, School of Life Science, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
3
Laboratory of Synaptic Mechanisms, Brain Mind Institute, School of Life Science, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland, and ralf.schneggenburger@epfl.ch.

Abstract

Ca(2+)-dependent transmitter release occurs in a fast and in a slow phase, but the differential roles of Ca(2+) buffers and Ca(2+) sensors in shaping release kinetics are still controversial. Replacing extracellular Ca(2+) by Sr(2+) causes decreased fast release but enhanced slow release at many synapses. Here, we established presynaptic Sr(2+) uncaging and made quantitative Sr(2+)- and Ca(2+)-imaging experiments at the mouse calyx of Held synapse, to reveal the interplay between Ca(2+) sensors and Ca(2+) buffers in the control of fast and slow release. We show that Sr(2+) activates the fast, Synaptotagmin-2 (Syt2) sensor for vesicle fusion with sixfold lower affinity but unchanged high cooperativity. Surprisingly, Sr(2+) also activates the slow sensor that remains in Syt2 knock-out synapses with a lower efficiency, and Sr(2+) was less efficient than Ca(2+) in the limit of low concentrations in wild-type synapses. Quantitative imaging experiments show that the buffering capacity of the nerve terminal is markedly lower for Sr(2+) than for Ca(2+) (~5-fold). This, together with an enhanced Sr(2+) permeation through presynaptic Ca(2+) channels (~2-fold), admits a drastically higher spatially averaged Sr(2+) transient compared with Ca(2+). Together, despite the lower affinity of Sr(2+) at the fast and slow sensors, the massively higher amplitudes of spatially averaged Sr(2+) transients explain the enhanced late release. This also allows us to conclude that Ca(2+) buffering normally controls late release and prevents the activation of the fast release sensor by residual Ca(2+).

KEYWORDS:

calcium buffering capacity; calcium sensor; endogenous fixed buffer; slow release sensor; strontium; synaptotagmin

PMID:
25232102
PMCID:
PMC6705322
DOI:
10.1523/JNEUROSCI.1990-14.2014
[Indexed for MEDLINE]
Free PMC Article

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