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J. Biol. Chem., Vol. 282, Issue 15, 11238-11245, April 13, 2007

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Calcium Influx and Mitochondrial Alterations at Synapses Exposed to Snake Neurotoxins or Their Phospholipid Hydrolysis Products^*

Michela Rigoni, Paola Pizzo, Giampietro Schiavo, Anne E. Weston, Giancarlo Zatti, Paola Caccin, Ornella Rossetto, Tullio Pozzan^¶, and Cesare Montecucco¹

From the Department of Biomedical Sciences and Consiglio Nazionale Ricerche Institute of Neuroscience, University of Padova, 35121 Padova, Italy, Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, London WC2A 3PX, United Kingdom, and ^¶Venetian Institute of Molecular Medicine, 35129 Padova, Italy

Snake presynaptic phospholipase A2 neurotoxins (SPANs) bind to the presynaptic membrane and hydrolyze phosphatidylcholine with generation of lysophosphatidylcholine (LysoPC) and fatty acid (FA). The LysoPC + FA mixture promotes membrane fusion, inducing the exocytosis of the ready-to-release synaptic vesicles. However, also the reserve pool of synaptic vesicles disappears from nerve terminals intoxicated with SPAN or LysoPC + FA. Here, we show that LysoPC + FA and SPANs cause a large influx of extracellular calcium into swollen nerve terminals, which accounts for the extensive synaptic vesicle release. This is paralleled by the change of morphology and the collapse of membrane potential of mitochondria within nerve bulges. These results complete the picture of events occurring at nerve terminals intoxicated by SPANs and define the LysoPC + FA lipid mixture as a novel and effective agonist of synaptic vesicle release.

Received for publication, October 31, 2006 , and in revised form, January 22, 2007.

^* This work was supported by grants from Telethon-Italia GGP06133, the University of Padova, FIRBRBNE01RHZM, and Cancer Research UK. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2 and Movies 1 and 2.

¹ To whom correspondence should be addressed: Dept. of Biomedical Sciences, University of Padova, Viale G. Colombo, 3, 35121 Padova, Italy. Tel.: 39-0498276058; Fax: 39-0498276049; E-mail: cesare.montecucco{at}unipd.it.

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