Alpha-latrotoxin stimulates a novel pathway of Ca2+-dependent synaptic exocytosis independent of the classical synaptic fusion machinery.
Alpha-latrotoxin induces neurotransmitter release by stimulating synaptic vesicle exocytosis via two mechanisms: (1) A Ca(2+)-dependent mechanism with neurexins as receptors, in which alpha-latrotoxin acts like a Ca(2+) ionophore, and (2) a Ca(2+)-independent mechanism with CIRL/latrophilins as receptors, in which alpha-latrotoxin directly stimulates the transmitter release machinery. Here, we show that the Ca(2+)-independent release mechanism by alpha-latrotoxin requires the synaptic SNARE-proteins synaptobrevin/VAMP and SNAP-25, and, at least partly, the synaptic active-zone protein Munc13-1. In contrast, the Ca(2+)-dependent release mechanism induced by alpha-latrotoxin does not require any of these components of the classical synaptic release machinery. Nevertheless, this type of exocytotic neurotransmitter release appears to fully operate at synapses, and to stimulate exocytosis of the same synaptic vesicles that participate in physiological action potential-triggered release. Thus, synapses contain two parallel and independent pathways of Ca(2+)-triggered exocytosis, a classical, physiological pathway that operates at the active zone, and a novel reserve pathway that is recruited only when Ca(2+) floods the synaptic terminal.
Deák
Ferenc
F
Department of Neuroscience and Molecular Genetics and Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9111, USA.
Liu
Xinran
X
Khvotchev
Mikhail
M
Li
Gang
G
Kavalali
Ege T
ET
Sugita
Shuzo
S
Südhof
Thomas C
TC
D000818:Animals; D001740:Black Widow Spider / Q000737:chemistry; D002118:Calcium / Q000502:physiology*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D005089:Exocytosis / Q000187:drug effects / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D013111:Spider Venoms / Q000302:isolation & purification / Q000494:pharmacology*; D013569:Synapses / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000502:physiology*
D013111:Spider Venoms; C020763:alpha-latrotoxin; D002118:Calcium; C038599:black widow spider venom