Characterization of hadrucalcin, a peptide from Hadrurus gertschi scorpion venom with pharmacological activity on ryanodine receptors

Periodo de realización: 1900/01/01 al 2009/01/01

Tipo: Artículo científico

Lugar(es) de estudio: Cuernavaca, Mor., México, Brasilia - Región Integrada de Desarrollo del DF y Entorno, Brasilia - Distrito Federal, Brasil, Madison, Wisconsin, EE. UU.
Resumen: "Background and purpose: Members of the calcin family, presently including imperatoxin A, maurocalcin, opicalcins andhemicalcin, are basic, 33-mer peptide activators of ryanodine receptors (RyRs), the calcium channels of the sarcoplasmicreticulum (SR) that provide the majority of calcium for muscle contraction. Here we describe hadrucalcin, a novel member ofthis family.Experimental approach: Hadrucalcin was isolated from the venom of Hadrurus gertschi. Amino acid sequence and mass weredetermined by Edman degradation and mass spectrometry respectively. A cDNA library was constructed to generate clones forDNA sequence determination. Biological activity of native toxin was confirmed with [3H]ryanodine binding, by using SR vesiclesfrom cardiac and skeletal muscle, and with single skeletal (RyR1) and cardiac (RyR2) channels reconstituted in lipid bilayers.Hadrucalcin was applied to intact ventricular myocytes to investigate effects on calcium transients. The secondary structure ofhadrucalcin was computer-modelled by using atomic coordinates from maurocalcin, a structurally similar peptide.Key results: Hadrucalcin is distinguished from previously described congeners by two additional amino acids in its primarysequence and the lack of prominent amphipathicity. Hadrucalcin activated RyRs with high affinity (EC50 = 37 nmol·L-1), induceda long-lasting subconductance state on RyR1 and RyR2, and rapidly (lag time ~2 s) penetrated ventricular cardiomyocytes,eliciting discharge of internal calcium stores and spontaneous contractions.Conclusions and implications: Hadrucalcin is a cell-permeant, powerful activator of RyRs, which has translational potential fortargeted delivery of drugs to RyR as novel therapeutic intervention in arrhythmogenic disease."

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