• Le 19 octobre 2018
    Institut de Recherche en Santé - 8 quai Moncousu - Nantes
    Amphithéâtre Denis Escande
  • Attention changement d'horaire
    15h

Scorpions, snakes, insecticides and coffee: new insights into the mechanisms of calcium-dependent arrhythmias

Scorpions, snakes, insecticides and coffee: new insights into the mechanisms of calcium-dependent arrhythmias

Hector Valdivia, MD, PhD, invited by Flavien Charpentier (Eq IIa)
Professor of Medicine, Division of Cardiology
Director of Cardiovascular Research Center , University of Wisconsin Medical School (Madison, USA)

Dr. Héctor Valdivia attended medical school at the National Autonomous University of Mexico (UNAM), in Mexico City, and then graduate school at the same university. In 1990 he obtained his PhD degree from his combined work at UNAM and Baylor College of Medicine in Houston, Texas. His PhD thesis was on the purification and characterization of scorpion toxins that block potassium channels, which started his career-long interest on ion channels of excitable membranes. After postdoctoral training at the University of Maryland-Baltimore,
Dr Valdivia joined the faculty of the University of Wisconsin-Madison in 1994, where he developed a strong program in cardiovascular physiology and pharmacology. From 2012 to 2017, he was appointed the Frank N. Wilson Professor of Cardiovascular Medicine of the University of Michigan. His current research focus is on intracellular calcium homeostasis and calcium channels, and the mechanisms that generate calcium-dependent arrhythmias. He uses multi-disciplinary approaches at the molecular, cellular and intact animal level for an integral study of physiological and pathophysiological calcium signaling in the heart. His work has been cited more than 7,000 times.

Hector Valdivia is currently in Paris for Fulbright Visiting Scholar program at Ana-Maria Gomez lab (Signalisation and Cardiovascular Physiopathology - Inserm UMR1180)


ABSTRACT

Ryanodine receptors (RyR) are sarcoplasmic reticulum Ca2+ release channels that play a critical role in Ca2+ signaling of excitable and non-excitable cells. RyRs owe their name to the fact that they were characterized in great part thanks to ryanodine, a plant alkaloid that binds to RyRs with high affinity and specificity. Ryanodine has been an invaluable ligand of RyRs, but its functional effects are complex and hamper its use in cellular studies. In search of novel ligands that could overcome some of the functional and structural disadvantages of ryanodine, we found in the venom of selected scorpions a set of peptide ligands displaying high affinity and exquisite selectivity against RyRs. These peptides were dubbed calcins for their capacity to target RyRs, a calcium-release channel. The defining characteristic of calcins is their capacity to stabilize RyR openings in a long-lasting subconducting state. This effect is nearly analogous to that of ryanodine, but unlike ryanodine, calcins bind rapidly to RyRs (fast association rate), freely dissociate from their binding site (reversible effect), display a dose- and sequence-variable effect, and are amenable for derivatization without undergoing major loss in receptor affinity.  Calcins also modulate intracellular Ca2+ in intact cardiomyocytes with remarkable speed and with several degrees of potency, thus entering the field as cell-penetrating peptides (CPP) RyR-specific Ca2+ mobilizer of high dynamic range. In this seminar, we will discuss the effect of calcins on intact cardiomyocytes and propose a novel paradigm to prevent cardiac arrhythmias in animal models of catecholaminergic polymorphic ventricular tachycardia.