Category Ranking
98%
Total Visits
921
Avg Visit Duration
2 minutes
Citations
20
Article Abstract
A new ryanodine-binding inhibitor, verticilide, was isolated from the cultured broth of a fungus, Verticillium sp. FKI-1033. It is a 24-membered ring cyclic depsipeptide, its structure being elucidated as cyclo[(2R)-2-hydroxyheptanoyl-N-methyl- L-alanyl](4). Verticilide inhibited ryanodine binding to ryanodine receptors in the cockroach at an IC(50) value of 4.2 microM, whereas inhibition against mouse ryanodine receptors was weak (IC(50)=53.9 microM).
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1038/ja.2009.126 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
-Verticilide B1 Inhibits Type 2 Ryanodine Receptor Channels and is Antiarrhythmic in Mice.
Mol Pharmacol
February 2024
Vanderbilt Center for Arrhythmia Research and Therapeutics, Division of Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee (A.G., T.Q.D. K.K., D.J.B., P.A.R., B.C.K.); Vanderbilt Department of Chemistry and Institute of Chemical Biology, Vanderbilt University, Nashvill
Intracellular Ca leak from cardiac ryanodine receptor (RyR2) is an established mechanism of sudden cardiac death (SCD), whereby dysregulated Ca handling causes ventricular arrhythmias. We previously discovered the RyR2-selective inhibitor (+)-verticilide (-1), a 24-membered cyclooligomeric depsipeptide that is the enantiomeric form of a natural product (-(-)-verticilide). Here, we examined its 18-membered ring-size oligomer (-verticilide B1; "-B1") in RyR2 single channel and [H]ryanodine binding assays, and in cardiomyocytes and mice, a gene-targeted model of SCD.
View Article and Find Full Text PDFScreening for Novel Type 2 Ryanodine Receptor Inhibitors by Endoplasmic Reticulum Ca Monitoring.
Mol Pharmacol
December 2023
Department of Cellular and Molecular Pharmacology (M.T., M.K., T.M., T.S., N.K.) and Department of Clinical Laboratory Medicine (M.S.), Juntendo University Graduate School of Medicine, Tokyo, Japan; Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo, Japan (M.I.
Type 2 ryanodine receptor (RyR2) is a Ca release channel on the endoplasmic (ER)/sarcoplasmic reticulum that plays a central role in the excitation-contraction coupling in the heart. Hyperactivity of RyR2 has been linked to ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia and heart failure, where spontaneous Ca release via hyperactivated RyR2 depolarizes diastolic membrane potential to induce triggered activity. In such cases, drugs that suppress RyR2 activity are expected to prevent the arrhythmias, but there is no clinically available RyR2 inhibitors at present.
View Article and Find Full Text PDFUnlabelled: Ca leak from cardiac ryanodine receptor (RyR2) is an established mechanism of sudden cardiac death (SCD), whereby dysregulated Ca handling causes ventricular arrhythmias. We previously discovered the RyR2-selective inhibitor (+)-verticilide ( -1), a 24-membered cyclooligomeric depsipeptide that is the enantiomeric form of a natural product ( -(-)-verticilide). Here, we examined its 18-membered ring-size oligomer ( -verticilide B1; " -B1") in single RyR2 channel assays, [ H]ryanodine binding assays, and in cardiomyocytes and mice, a gene-targeted model of SCD.
View Article and Find Full Text PDFStatin activation of skeletal ryanodine receptors (RyR1) is a class effect but separable from HMG-CoA reductase inhibition.
Br J Pharmacol
November 2022
Department of Pharmacology, University of Oxford, Oxford, UK.
Background And Purpose: Statins, inhibitors of HMG-CoA reductase, are mainstay treatment for hypercholesterolaemia. However, muscle pain and weakness prevent many patients from benefiting from their cardioprotective effects. We previously demonstrated that simvastatin activates skeletal ryanodine receptors (RyR1), an effect that could be important in initiating myopathy.
View Article and Find Full Text PDFCardiac ryanodine receptor N-terminal region biosensors identify novel inhibitors via FRET-based high-throughput screening.
J Biol Chem
January 2022
Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota, USA. Electronic address:
The N-terminal region (NTR) of ryanodine receptor (RyR) channels is critical for the regulation of Ca release during excitation-contraction (EC) coupling in muscle. The NTR hosts numerous mutations linked to skeletal (RyR1) and cardiac (RyR2) myopathies, highlighting its potential as a therapeutic target. Here, we constructed two biosensors by labeling the mouse RyR2 NTR at domains A, B, and C with FRET pairs.
View Article and Find Full Text PDF