Ryanoids and imperatoxin affect the modulation of cardiac ryanodine receptors by dihydropyridine receptor Peptide A.

Biochimica Et Biophysica Acta
Maura PortaJulio A Copello

Abstract

Ca(2+)-entry via L-type Ca(2+) channels (DHPR) is known to trigger ryanodine receptor (RyR)-mediated Ca(2+)-release from sarcoplasmic reticulum (SR). The mechanism that terminates SR Ca(2+) release is still unknown. Previous reports showed evidence of Ca(2+)-entry independent inhibition of Ca(2+) sparks by DHPR in cardiomyocytes. A peptide from the DHPR loop II-III (PepA) was reported to modulate isolated RyRs. We found that PepA induced voltage-dependent "flicker block" and transition to substates of fully-activated cardiac RyRs in planar bilayers. Substates had less voltage-dependence than block and did not represent occupancy of a ryanoid site. However, ryanoids stabilized PepA-induced events while PepA increased RyR2 affinity for ryanodol, which suggests cooperative interactions. Ryanodol stabilized Imperatoxin A (IpTx(A)) binding but when IpTx(A) bound first, it prevented ryanodol binding. Moreover, IpTx(A) and PepA excluded each other from their sites. This suggests that IpTx(A) generates a vestibular gate (either sterically or allosterically) that prevents access to the peptides and ryanodol binding sites. Inactivating gate moieties ("ball peptides") from K(+) and Na(+) channels (ShakerB and KIFMK, respectively) induced ...Continue Reading

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Citations

Jun 15, 2011·Molecular Pharmacology·Jake T Neumann, Julio A Copello
Jul 13, 2012·American Journal of Physiology. Cell Physiology·Maura PortaJulio A Copello
Dec 18, 2009·PloS One·Paula L Diaz-Sylvester, Julio A Copello
Oct 7, 2009·Biophysical Journal·Charalambos SigalasRebecca Sitsapesan
Jul 31, 2013·Toxicon : Official Journal of the International Society on Toxinology·V Quintero-HernándezL D Possani
Nov 1, 2011·PloS One·Paula L Diaz-SylvesterJulio A Copello

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