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Pharmaceuticals 2010, 3(4), 1093-1107;

Imperatoxin A, a Cell-Penetrating Peptide from Scorpion Venom, as a Probe of Ca2+-Release Channels/Ryanodine Receptors

Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, Morelos 62271,Mexico
Department of Physiology, University of Wisconsin Medical School, Madison, WI 53706, USA
These authors contributed equally to this study.
Author to whom correspondence should be addressed.
Received: 18 March 2010 / Accepted: 11 April 2010 / Published: 13 April 2010
(This article belongs to the Special Issue Cell-penetrating Peptides 2012)
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Scorpion venoms are rich in ion channel-modifying peptides, which have proven to be invaluable probes of ion channel structure-function relationship. We previously isolated imperatoxin A (IpTxa), a 3.7 kDa peptide activator of Ca2+-release channels/ryanodine receptors (RyRs) [1,2,3] and founding member of the calcin family of scorpion peptides. IpTxa folds into a compact, mostly hydrophobic molecule with a cluster of positively-charged, basic residues polarized on one side of the molecule that possibly interacts with the phospholipids of cell membranes. To investigate whether IpTxa permeates external cellular membranes and targets RyRs in vivo, we perfused IpTxa on intact cardiomyocytes while recording field-stimulated intracellular Ca2+ transients. To further investigate the cell-penetrating capabilities of the toxin, we prepared thiolated, fluorescent derivatives of IpTxa. Biological activity and spectroscopic properties indicate that these derivatives retain high affinity for RyRs and are only 5- to 10-fold less active than native IpTxa. Our results demonstrate that IpTxa is capable of crossing cell membranes to alter the release of Ca2+ in vivo, and has the capacity to carry a large, membrane-impermeable cargo across the plasma membrane, a finding with exciting implications for novel drug delivery. View Full-Text
Keywords: imperatoxin; ryanodine receptors; cell-penetrating peptide; calcin; drug delivery imperatoxin; ryanodine receptors; cell-penetrating peptide; calcin; drug delivery

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Gurrola, G.B.; Capes, E.M.; Zamudio, F.Z.; Possani, L.D.; Valdivia, H.H. Imperatoxin A, a Cell-Penetrating Peptide from Scorpion Venom, as a Probe of Ca2+-Release Channels/Ryanodine Receptors. Pharmaceuticals 2010, 3, 1093-1107.

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