title: Eudistomin D and penaresin derivatives as modulators of ryanodine receptor channels and sarcoplasmic reticulum Ca2+ ATPase in striated muscle.
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.
authors.affiliation: 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.).
authors.forename: Paula L
authors.initials: PL
authors.lastname: Diaz-Sylvester
authors.forename: Maura
authors.initials: M
authors.lastname: Porta
authors.forename: Vanessa V
authors.initials: VV
authors.lastname: Juettner
authors.forename: Yuanzhao
authors.initials: Y
authors.lastname: Lv
authors.forename: Sidney
authors.initials: S
authors.lastname: Fleischer
authors.forename: Julio A
authors.initials: JA
authors.lastname: Copello
mesh_terms: D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002120:Calcium Channel Agonists / Q000737:chemistry / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000737:chemistry / Q000494:pharmacology; D000252:Calcium-Transporting ATPases / Q000378:metabolism*; D002243:Carbolines / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D026121:Indole Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D008051:Lipid Bilayers / Q000737:chemistry; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D011485:Protein Binding; D011817:Rabbits; D019837:Ryanodine Receptor Calcium Release Channel / Q000737:chemistry / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*
chemical_list: D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D002243:Carbolines; D026121:Indole Alkaloids; D008051:Lipid Bilayers; D019837:Ryanodine Receptor Calcium Release Channel; C520303:eudistomin D; C060741:9-methyl-7-bromoeudistomin D; D002110:Caffeine; D000252:Calcium-Transporting ATPases; D002118:Calcium