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The Journal of Neuroscience, July 8, 2009, 29(27):8639-8648; doi:10.1523/JNEUROSCI.0898-09.2009

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Cellular/Molecular
-Latrotoxin Stimulates a Novel Pathway of Ca²⁺-Dependent Synaptic Exocytosis Independent of the Classical Synaptic Fusion Machinery

Ferenc Deák,^1,3 Xinran Liu,¹ Mikhail Khvotchev,¹ Gang Li,^4,5 Ege T. Kavalali,¹ Shuzo Sugita,^4,5 and Thomas C. Südhof^1,2,5,6,7

Departments of ¹Neuroscience and ²Molecular Genetics and ³Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center, Dallas, Texas 75390-9111, ⁴Division of Fundamental Neurobiology, Toronto Western Research Institute, University Health Network, Toronto, Ontario M5T 2S8, Canada, ⁵Department of Physiology, Faculty of Medicine, University of Toronto, Ontario M5S 1A8, Canada, and ⁶Department of Cellular & Molecular Physiology and ⁷Howard Hughes Medical Institute, Stanford University, Palo Alto, California 94304-5543

Correspondence should be addressed to Thomas C. Südhof, Department of Cellular & Molecular Physiology, Stanford University, 1050 Arastradero Road, B249, Palo Alto, CA 94304-5543. Email: tcs1{at}stanford.edu

-Latrotoxin induces neurotransmitter release by stimulating synaptic vesicle exocytosis via two mechanisms: (1) A Ca²⁺-dependent mechanism with neurexins as receptors, in which -latrotoxin acts like a Ca²⁺ ionophore, and (2) a Ca²⁺-independent mechanism with CIRL/latrophilins as receptors, in which -latrotoxin directly stimulates the transmitter release machinery. Here, we show that the Ca²⁺-independent release mechanism by -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 Ca²⁺-dependent release mechanism induced by -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 Ca²⁺-triggered exocytosis, a classical, physiological pathway that operates at the active zone, and a novel reserve pathway that is recruited only when Ca²⁺ floods the synaptic terminal.

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Received Feb. 22, 2009; revised May 25, 2009; accepted June 3, 2009.

Correspondence should be addressed to Thomas C. Südhof, Department of Cellular & Molecular Physiology, Stanford University, 1050 Arastradero Road, B249, Palo Alto, CA 94304-5543. Email: tcs1{at}stanford.edu

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