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Volume 272, Number 18, Issue of May 2, 1997 pp. 11886-11894
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

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The Mechanism of Inhibition of Ryanodine Receptor Channels by Imperatoxin I, a Heterodimeric Protein from the Scorpion Pandinus imperator

(Received for publication, February 6, 1997)

Fernando Z. Zamudio , Renaud Conde , Carolina Arévalo ^§ , Baltazar Becerril , Brian M. Martin ^§¶ , Hector H. Valdivia ^§ and Lourival D. Possani

From the ^§ Department of Physiology, University of Wisconsin Medical School, Madison, Wisconsin 53706, the  Department of Molecular Recognition and Structural Biology, Biotechnology Institute, National Autonomous University of Mexico, Cuernavaca, Morelos 62271, Mexico, and the ^¶ National Institute of Mental Health, Unit on Molecular Structures, Bethesda, Maryland 20892

We present an in-depth analysis of the structural and functional properties of Imperatoxin I (IpTx_i), an ~15-kDa protein from the venom of the scorpion Pandinus imperator that inhibits Ca²⁺ release channel/ryanodine receptor (RyR) activity (Valdivia, H. H., Kirby, M. S., Lederer, W. J., and Coronado, R. (1992) Proc. Natl. Acad. Sci. U.S.A. 89, 12185-12189). A cDNA library was prepared from the venomous glands of this scorpion and used to clone the gene encoding IpTx_i. From a single continuous messenger RNA, the information coding for the toxin is translated into two mature polypeptide subunits after elimination of a basic pentapeptide. The IpTx_i dimer consists of a large subunit (104-amino acid residues) with phospholipase A₂ (PLA₂) activity covalently linked by a disulfide bond to a smaller (27 amino acid residues), structurally unrelated subunit. Thus, IpTx_i is a heterodimeric protein with lipolytic action, a property that is only shared with -bungarotoxins, a group of neurotoxins from snake venoms. The enzymatic subunit of IpTx_i is highly homologous to PLA₂ from bee (Apis mellifera) and lizard (Heloderma horridum) venoms. The small subunit has no significant similarity to any other known peptide, including members of the Kunitz protease inhibitors superfamily that target the lipolytic effect of -bungarotoxins. A synthetic peptide with amino acid sequence identical to that of the small subunit failed to inhibit RyR. On the other hand, treatment of IpTx_i with p-bromophenacylbromide, a specific inhibitor of PLA₂ activity, greatly reduced the capacity of IpTx_i to inhibit RyRs. These results suggested that a lipid product of PLA₂ activity, more than a direct IpTx_i-RyR interaction, was responsible for RyR inhibition.

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