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Cardiac Myosin - Europe PMC

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Last Updated: 16 January 2023

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Conformational changes linked to ADP release from human cardiac myosin bound to actin-tropomyosin.

Following adhesion to the thin filament, u03b2-cardiac myosin couples ATP-hydrolysis to conformational rearrangements in the myosin motor that results in myofilament shifting and cardiac contraction. Small improvements in the nucleotide-binding site are due to tighter body movements of the myosin converter domain and a 16-degree lever arm swing, according to targeted body movements. Our systems provide a mechanistic framework for investigating the cardiac myosin motor's force-sensing mechanism.

Source link: https://europepmc.org/article/MED/36633586


Single Molecule Mechanics and Kinetics of Cardiac Myosin Interacting with Regulated Thin Filaments

During systole and then relaxes during diastole, the heart creates pressure to pump blood to the body during systole and then relaxes during diastole. In some muscle and non-muscle myosins, regulatory proteins on actin tune the kinetics, mechanics, and load-dependence of the myosin working stroke; however, it is unknown if or how thin filament regulatory proteins tune the cardiac myosin motor mechanics. We discovered that regulatory proteins regulated the calcium-dependent interactions between myosin and the thin filament in a calcium-dependent manner. We also analyzed cardiac myosin plasma concentrations at physiologically relevant ATP levels using an isometric optical clamp, and we found that thin filament regulatory proteins did not influence either the identity or magnitude of myosin's primary load-dependent transition. Interestingly, thin filament regulatory proteins have a small effect on actomyosin dissociation kinetics at low ATP levels, suggesting a mechanism other than simple steric blocking. Significance Statement Significance Statement The molecular motor u03b2-cardiac myosin, which pulls on thin filaments composed of actin and the regulatory proteins troponin and tropomyosin, which contributes to heart contractions. We find that regulatory proteins do not influence the physical or load-dependent kinetics of the working stroke at physiologically relevant ATP concentrations; however, they can influence kinetics at low ATP levels, suggesting a process other than simple steric blocking.

Source link: https://europepmc.org/article/PPR/PPR595329


The Novel Cardiac Myosin Activator Danicamtiv Improves Cardiac Systolic Function at the Expense of Diastolic Dysfunction In Vitro and In Vivo: Implications for Clinical Applications

In enzymatically isolated canine cardiomyocytes and cerebral Ca2+ measurements, changes in sarcomere length and intracellular Ca2+ levels were monitored in parallel, and detailed echocardiographic studies were carried out in anesthetized rats in the absence or presence of danicamtiv. The systolic and diastolic sarcomere lengths slowed, but contraction and relaxation kinetics slowed as danicamtiv concentrations slowed, even with changes in intracellular Ca2+ transients in vitro. However, the systolic ejection time was greatly prolonged, the ratio of diastolic to systolic length was reduced, and signs of diastolic dysfunction were also present during danicamtiv therapy in vivo.

Source link: https://europepmc.org/article/MED/PMC9820393


The Novel Cardiac Myosin Activator Danicamtiv Improves Cardiac Systolic Function at the Expense of Diastolic Dysfunction In Vitro and In Vivo: Implications for Clinical Applications.

With increasing danicamtiv concentrations without changes in intracellular Ca 2+ transients in vitro, the systolic and diastolic sarcomere lengths decreased; contraction and relaxation kinetics slowed; contraction and relaxation kinetics slowed down with decreasing danicamtiv kinetics. Nonetheless, the systolic ejection time was significantly increased, the ratio of diastolic to systolic duration was reduced, and signs of diastolic dysfunction were also noted during vivo danicamtiv therapy. Taken together, danicamtiv enhances cardiac systolic function, but it can also reduce diastolic outcomes, particularly at high drug concentrations.

Source link: https://europepmc.org/article/MED/36613900

* Please keep in mind that all text is summarized by machine, we do not bear any responsibility, and you should always check original source before taking any actions

* Please keep in mind that all text is summarized by machine, we do not bear any responsibility, and you should always check original source before taking any actions