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J. Biol. Chem., Vol. 279, Issue 12, 11853-11862, March 19, 2004

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Multiple Actions of Imperatoxin A on Ryanodine Receptors

INTERACTIONS WITH THE II-III LOOP "A" FRAGMENT^*

Angela F. Dulhunty, Suzanne M. Curtis, Sarah Watson, Louise Cengia¶, and Marco G. Casarotto

From the Division of Molecular Bioscience, John Curtin School of Medical Research and Research School of Chemistry, Canberra and ^¶Biotron Limited, Eggleston Rd., Australian National University, P. O. Box 334, Australian Capital Territory 2601, Australia

Imperatoxin A is a high affinity activator of ryanodine receptors. The toxin contains a positively charged surface structure similar to that of the A fragment of skeletal dihydropyridine receptors (peptide A), suggesting that the toxin and peptide could bind to a common site on the ryanodine receptor. However, the question of a common binding site has not been resolved, and the concentration dependence of the actions of the toxin has not been fully explored. We characterize two novel high affinity actions of the toxin on the transient gating of cardiac and skeletal channels, in addition to the well documented lower affinity induction of prolonged substates. Transient activity was (a) enhanced with 0.2-10 nM toxin and (b) depressed by >50 nM toxin. The toxin at 1 nM enhanced Ca²⁺ release from SR in a manner consistent with two independent activation processes. The effects of the toxin on transient activity, as well as the toxin-induced substate, were independent of cytoplasmic Ca²⁺ or Mg²⁺ concentrations or the presence of adenine nucleotide and were seen in diisothiocyanostilbene-2',2'-disulfonic acid-modified channels. Peptide A activated skeletal and cardiac channels with 100 nM cytoplasmic Ca²⁺ and competed with Imperatoxin A in the high affinity enhancement of transient channel activity and Ca²⁺ release from SR. In contrast to transient activity, prolonged substate openings induced by the toxin were not altered in the presence of peptide A. The results suggest that Imperatoxin A has three independent actions on ryanodine receptor channels and competes with peptide A for at least one action.

Received for publication, September 22, 2003 , and in revised form, December 16, 2003.

^* The work was supported by grants form the National Heart Foundation of Australian (Grant G-01C-0296) and the National Health and Medical Research Council (Grant 224235). 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.

To whom correspondence should be addressed. Tel.: 61-6-125-4491; Fax: 61-6-125-4761; E-mail: angela.dulhunty{at}anu.edu.au

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