title: K201 (JTV519) is a Ca2+-Dependent Blocker of SERCA and a Partial Agonist of Ryanodine Receptors in Striated Muscle.
abstract: K201 (JTV-519) may prevent abnormal Ca(2+) leak from the sarcoplasmic reticulum (SR) in the ischemic heart and skeletal muscle (SkM) by stabilizing the ryanodine receptors (RyRs; RyR1 and RyR2, respectively). We tested direct modulation of the SR Ca(2+)-stimulated ATPase (SERCA) and RyRs by K201. In isolated cardiac and SkM SR microsomes, K201 slowed the rate of SR Ca(2+) loading, suggesting potential SERCA block and/or RyR agonism. K201 displayed Ca(2+)-dependent inhibition of SERCA-dependent ATPase activity, which was measured in microsomes incubated with 200, 2, and 0.25 µM Ca(2+) and with the half-maximal K201 inhibitory doses (IC50) estimated at 130, 19, and 9 µM (cardiac muscle) and 104, 13, and 5 µM (SkM SR). K201 (≥5 µM) increased RyR1-mediated Ca(2+) release from SkM microsomes. Maximal K201 doses at 80 µM produced ∼37% of the increase in SkM SR Ca(2+) release observed with the RyR agonist caffeine. K201 (≥5 µM) increased the open probability (Po) of very active ("high-activity") RyR1 of SkM reconstituted into bilayers, but it had no effect on "low-activity" channels. Likewise, K201 activated cardiac RyR2 under systolic Ca(2+) conditions (∼5 µM; channels at Po ∼0.3) but not under diastolic Ca(2+) conditions (∼100 nM; Po < 0.01). Thus, K201-induced the inhibition of SR Ca(2+) leak found in cell-system studies may relate to potentially potent SERCA block under resting Ca(2+) conditions. SERCA block likely produces mild SR depletion in normal conditions but could prevent SR Ca(2+) overload under pathologic conditions, thus precluding abnormal RyR-mediated Ca(2+) release.
authors.affiliation: Department of Pharmacology (Y.L.D., P.L.D.-S., J.A.C.) and Center for Clinical Research (P.L.D.-S.), Southern Illinois University School of Medicine, Springfield, Illinois.
authors.forename: Yuanzhao L
authors.initials: YL
authors.lastname: Darcy
authors.affiliation: Department of Pharmacology (Y.L.D., P.L.D.-S., J.A.C.) and Center for Clinical Research (P.L.D.-S.), Southern Illinois University School of Medicine, Springfield, Illinois.
authors.forename: Paula L
authors.initials: PL
authors.lastname: Diaz-Sylvester
authors.affiliation: Department of Pharmacology (Y.L.D., P.L.D.-S., J.A.C.) and Center for Clinical Research (P.L.D.-S.), Southern Illinois University School of Medicine, Springfield, Illinois jcopello@siumed.edu.
authors.forename: Julio A
authors.initials: JA
authors.lastname: Copello
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002120:Calcium Channel Agonists / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015640:Ion Channel Gating / Q000187:drug effects; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D054792:Muscle, Striated / Q000187:drug effects / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D011817:Rabbits; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D034421:Sus scrofa; D013841:Thiazepines / Q000494:pharmacology*
chemical_list: D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D019837:Ryanodine Receptor Calcium Release Channel; D013841:Thiazepines; C109183:K201 compound; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium