Positive Cardiac Inotrope, Omecamtiv Mecarbil, Activates Muscle Despite Suppressing the Myosin Working Stroke
| Autor: | Bipasha Barua, E. Michael Ostap, Michael J. Greenberg, Yale E. Goldman, Donald A. Winkelmann, Michael S. Woody |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Inotrope Cardiac output Cardiotonic Agents Optical Tweezers Swine Science Drug Evaluation Preclinical General Physics and Astronomy macromolecular substances Pharmacology Myosins Inhibitory postsynaptic potential General Biochemistry Genetics and Molecular Biology Cell Line chemistry.chemical_compound 03 medical and health sciences Mice 0302 clinical medicine Adenosine Triphosphate Myosin medicine Animals Urea lcsh:Science Actin 030304 developmental biology 0303 health sciences Multidisciplinary Chemistry business.industry Activator (genetics) Cardiac myosin General Chemistry medicine.disease Omecamtiv mecarbil 030104 developmental biology Heart failure lcsh:Q business Adenosine triphosphate Monte Carlo Method 030217 neurology & neurosurgery |
| Zdroj: | Nature Communications, Vol 9, Iss 1, Pp 1-11 (2018) |
| DOI: | 10.1101/298141 |
| Popis: | Omecamtiv mecarbil (OM) is a positive cardiac inotrope in phase-3 clinical trials for treatment of heart failure. Although initially described as a direct myosin activator, subsequent studies are at odds with this description and do not explain OM-mediated increases in cardiac performance. Here we show, via single-molecule, biophysical experiments on cardiac myosin, that OM suppresses myosin’s working stroke and prolongs actomyosin attachment 5-fold, which explains inhibitory actions of the drug observed in vitro. OM also causes the actin-detachment rate to become independent of both applied load and ATP concentration. Surprisingly, increased myocardial force output in the presence of OM can be explained by cooperative thin-filament activation by OM-inhibited myosin molecules. Selective suppression of myosin is an unanticipated route to muscle activation that may guide future development of therapeutic drugs. |
| Databáze: | OpenAIRE |
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