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J Biol Chem, Vol. 273, Issue 32, 20046-20051, August 7, 1998

Isolation of a Member of the Neurotoxin/Cytotoxin Peptide Family from Xenopus laevis Skin Which Activates Dihydropyridine-sensitive Ca²⁺ Channels in Mammalian Epithelial Cells

R. John Macleod, Peter Lembessis, Susan James^¶, and Hugh P. J. Bennett^¶

From the ^¶ Endocrine Laboratory, Royal Victoria Hospital, Montreal, Quebec H3A 1A1,  Gastroenterology Division, Department of Pediatrics, Montreal Childrens Hospital Research Institute, and Faculty of Medicine, McGill University, Montreal, Quebec H3H 1P3, Canada

We have used a sensitive bioassay of calcium-mediated volume changes in mammalian absorptive intestinal epithelial cells to screen extracts of the skin of the amphibian Xenopus laevis for the presence of factors affecting ion transport. A 66-residue peptide, purified using reversed-phase high performance liquid chromatography techniques, caused isotonic volume reduction of guinea pig jejunal villus cells in suspension. This volume reduction required extracellular Ca²⁺ and was prevented by the dihydropyridine-sensitive Ca²⁺ channel blocker niguldipine. Structural analysis demonstrated the presence of eight cysteines and a primary structure homologous to that of the neurotoxin/cytotoxin family found in the venom of certain poisonous snakes. The structure of the peptide was identical to that of xenoxin-1 purified from dorsal gland secretions of X. laevis (Kolbe, M., Huber A., Cordier, P., Rasmussen, U., Bouchon, B., Jaquinod, M., Blasak, R., Detot, E., and Kreil, G. (1993) J. Biol. Chem. 268, 16458-16464). Xenoxin-1 (10 nM) caused volume changes that required extracellular Ca²⁺ and were comparable in magnitude and direction to changes caused by BayK-8644 (100 nM), a dihydropyridine-sensitive Ca²⁺ channel agonist. The initial rate of dihydropyridine-sensitive ⁴⁵Ca²⁺ influx was substantially increased by xenoxin-1. Staurosporine (10 nM) prevented volume changes caused by ATP (250 µM) but had no effect on volume changes caused by BayK-8644 or xenoxin-1. We conclude that xenoxin-1 directly activated dihydropyridine-sensitive Ca²⁺ channels in villus cells and that a mammalian homologue to xenoxin-1 may exist.

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