1. Academic Validation
  2. Eudistomin D and penaresin derivatives as modulators of ryanodine receptor channels and sarcoplasmic reticulum Ca2+ ATPase in striated muscle

Eudistomin D and penaresin derivatives as modulators of ryanodine receptor channels and sarcoplasmic reticulum Ca2+ ATPase in striated muscle

  • Mol Pharmacol. 2014 Apr;85(4):564-75. doi: 10.1124/mol.113.089342.
Paula L Diaz-Sylvester 1 Maura Porta Vanessa V Juettner Yuanzhao Lv Sidney Fleischer Julio A Copello
Affiliations

Affiliation

  • 1 Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, Illinois (P.L.D.-S., V.V.J., Y.L., J.A.C.); Department of Physiology, Midwestern University, Chicago School of Osteopathic Medicine, Downers Grove, Illinois (M.P.); and Departments of Biological Sciences and Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee (S.F.).
Abstract

Eudistomin D (EuD) and penaresin (Pen) derivatives are bioactive Alkaloids from marine sponges found to induce CA(2+) release from striated muscle sarcoplasmic reticulum (SR). Although these Alkaloids are believed to affect ryanodine receptor (RyR) gating in a "caffeine-like" manner, no single-channel study confirmed this assumption. Here, EuD and MBED (9-methyl-7-bromoeudistomin D) were contrasted against caffeine on their ability to modulate the SR CA(2+) loading/leak from cardiac and skeletal muscle SR microsomes as well as the function of RyRs in planar bilayers. The effects of these Alkaloids on [(3)H]ryanodine binding and SR CA(2+) ATPase (SERCA) activity were also tested. MBED (1-5 μM) fully mimicked maximal activating effects of caffeine (20 mM) on SR CA(2+) leak. At the single-channel level, MBED mimicked the agonistic action of caffeine on cardiac RyR gating (i.e., stabilized long openings characteristic of "high-open-probability" mode). EuD was a partial agonist at the maximal doses tested. The tested Pen derivatives displayed mild to no agonism on RyRs, SR CA(2+) leak, or [(3)H]ryanodine binding studies. Unlike caffeine, EuD and some Pen derivatives significantly inhibited SERCA at concentrations required to modulate RyRs. Instead, MBED's affinity for RyRs (EC50 ∼ 0.5 μM) was much larger than for SERCA (IC50 > 285 μM). In conclusion, MBED is a potent RyR agonist and, potentially, a better choice than caffeine for microsomal and cell studies due to its reported lack of effects on adenosine receptors and phosphodiesterases. As a high-affinity caffeine-like probe, MBED could also help identify the caffeine-binding site in RyRs.

Figures
Products