The Myosin Duty Ratio Tunes the Calcium Sensitivity and Cooperative Activation of the Thin Filament

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• 作者：Milad Webb ; Del R. Jackson ; Jr. ; Travis J. Stewart ; Samuel P. Dugan ; Michael S. Carter ; Christine R. Cremo ; Josh E. Baker
• 刊名：Biochemistry
• 出版年：2013
• 出版时间：September 17, 2013
• 年：2013
• 卷：52
• 期：37
• 页码：6437-6444
• 全文大小：346K
• 年卷期：v.52,no.37(September 17, 2013)
• ISSN：1520-4995

文摘

In striated muscle, calcium binding to the thin filament (TF) regulatory complex activates actin鈥搈yosin ATPase activity, and actin鈥搈yosin kinetics in turn regulates TF activation. However, a quantitative description of the effects of actin鈥搈yosin kinetics on the calcium sensitivity (pCa₅₀) and cooperativity (n_H) of TF activation is lacking. With the assumption that TF structural transitions and TF鈥搈yosin binding transitions are inextricably coupled, we advanced the principles established by Kad et al. [Kad, N., et al. (2005) Proc. Natl. Acad. Sci. U.S.A. 102, 16990鈥?6995] and Sich et al. [Sich, N. M., et al. (2011) J. Biol. Chem. 285, 39150鈥?9159] to develop a simple model of TF regulation, which predicts that pCa₅₀ varies linearly with duty ratio and that n_H is maximal near physiological duty ratios. Using in vitro motility to determine the calcium sensitivity of TF sliding velocities, we measured pCa₅₀ and n_H at different myosin densities and in the presence of ATPase inhibitors. The observed effects of myosin density and actin鈥搈yosin duty ratio on pCa₅₀ and n_H are consistent with our model predictions. In striated muscle, pCa₅₀ must match cytosolic calcium concentrations and a maximal n_H optimizes calcium responsiveness. Our results indicate that pCa₅₀ and n_H can be predictably tuned through TF鈥搈yosin ATPase kinetics and that drugs and disease states that alter ATPase kinetics can, through their effects on calcium sensitivity, alter the efficiency of muscle contraction.