Steric-model for activation of muscle thin filaments

Vibert, Peter; Craig, Roger; Lehman, William

doi:10.1006/jmbi.1996.0800

Cited by 440 publications

(582 citation statements)

References 31 publications

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“…Mechanistically, this likely would be mediated through tropomyosin. There is good evidence that tropomyosin can physically occupy the stereospecific and nonstereospecific myosin binding sites on actin, lending structural support for the block-closed-open thin-filament states (27). Because the HCM-associated mutant TnTs tested in the present study are located in a domain of TnT thought to be critical for tropomyosin interaction (Figure 1a and ref.…”

Section: Figuresupporting

confidence: 60%

Identification of a contractile deficit in adult cardiac myocytes expressing hypertrophic cardiomyopathy–associated mutant troponin T proteins

Rust¹,

Albayya²,

Metzger³

1999

J. Clin. Invest.

100

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Section: Figuresupporting

confidence: 60%

Identification of a contractile deficit in adult cardiac myocytes expressing hypertrophic cardiomyopathy–associated mutant troponin T proteins

Rust¹,

Albayya²,

Metzger³

1999

J. Clin. Invest.

100

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“…It is unclear why a modest increase in apparent affinity occurred instead, but the effect is small in any case. DISCUSSION The thin filament has at least three conformations: an inhibited state in the presence of EGTA, a Ca 2ϩ -induced state, and an active state observed in the presence of strongly binding myosin cross-bridges (35)(36)(37). These structures have been compared with three-dimensional reconstructions of myosin S1-decorated thin filaments (38,39), leading to the conclusion that tropomyosin interferes with the binding site for myosin S1 in the inhibited state and (to a lesser extent) in the Ca 2ϩ state but not in the active state.…”

Section: Mgatpase Activation As a Function Of The Free Ca 2ϩ Concentrmentioning

confidence: 99%

“…5 is also applicable in muscle fibers. An early kinetic step producing strong myosin binding can be expected to alter the position of the tropomyosin strand and raise the Ca 2ϩ affinity of adjacent troponin(s) (36,56). The Ca 2ϩ dependence of force generation kinetics can be explained if the concentration-dependent binding of additional Ca 2ϩ to adjacent troponin(s) alters the rate constants for completion of the power stroke and/or reversal of the early transition.…”

Section: Mgatpase Activation As a Function Of The Free Ca 2ϩ Concentrmentioning

confidence: 99%

Cooperative Effect of Calcium Binding to Adjacent Troponin Molecules on the Thin Filament-Myosin Subfragment 1 MgATPase Rate

Butters

Tobacman

1997

Journal of Biological Chemistry

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The myosin subfragment 1 (S1) MgATPase rate was measured using thin filaments with known extents of Ca 2؉ binding controlled by varying the ratio of native cardiac troponin versus an inhibitory troponin with a mutation in the sole regulatory Ca 2؉ binding site of troponin C. Fractional MgATPase activation was less than the fraction of troponins that bound Ca 2؉ , implying a cooperative effect of bound Ca 2؉ on cross-bridge cycling. Addition of phalloidin did not alter cooperative effects between bound Ca 2؉ molecules in the presence or absence of myosin S1. When the myosin S1 concentration was raised sufficiently to introduce cooperative myosin-myosin effects, lower Ca 2؉ concentrations were needed to activate the MgATPase rate. MgATPase activation remained less than Ca 2؉ binding, implying a true, not just an apparent, increase in Ca 2؉ affinity. MgATPase activation by Ca 2؉ was more cooperative than could be explained by cooperativeness of overall Ca 2؉ binding, the discrepancy between Ca 2؉ binding and MgATPase activation, or interactions between myosins. The results suggest the thin filament-myosin S1 MgATPase cycle requires calcium binding to adjacent troponin molecules and that this binding is cooperatively promoted by a single cycling cross-bridge. This mechanism is a potential explanation for Ca 2؉ -mediated regulation of crossbridge kinetics in muscle fibers.Just as isometric tension is cooperatively activated by Ca 2ϩ , so is the cardiac thin filament-myosin S1 1 MgATPase rate, even under conditions where there is no cooperativity in myosin S1 binding (1, 2). A possible explanation for this behavior is that ATPase activation is proportional to Ca 2ϩ binding to the many TnCs on each thin filament and that this calcium binding is cooperative (3). We tested the idea that Ca 2ϩ binding and MgATPase activation are proportional and found to the contrary that they are not. Instead, fractional MgATPase activation was considerably less than fractional Ca 2ϩ binding and more closely paralleled the number of pairs of adjacent troponins with Ca 2ϩ bound to both.To accomplish the above experiment, we employ a constitutively inhibitory form of cardiac troponin containing an inactivating mutation of the sole regulatory site of TnC, site II (4). This troponin, designated CBMII-Tn, results in a low thin filament-myosin S1 MgATPase rate that is not increased by the addition of Ca 2ϩ , analogous to previous results in which a similar TnC mutant was exchanged into myofibrils or muscle fibers (5-7). CBMII-Tn binds to actin-tropomyosin with an affinity identical to that of normal troponin in the absence of Ca 2ϩ . This binding, which is very tight for both normal troponin and for 8,9), permits the present report in which thin filaments are assembled with defined mixtures of normal troponin and CBMII-Tn. In the presence of saturating Ca 2ϩ concentrations, such thin filaments exhibit a fractional saturation of the TnC regulatory sites that is experimentally controllable by varying the relative concentrations of the two forms ...

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“…One may think that the mechanism is clear from the well-known steric-blocking model (1,35); Ca 2ϩ binds to TnC, TnI switches from actin to TnC, and TnT and Tm undergo conformational changes enabling cross bridges to interact in a force-generating manner with actin. However, it remains unclear in which order these events should be reversed during relaxation.…”

mentioning

confidence: 99%

Calcium regulation of troponin and its role in the dynamics of contraction and relaxation

Stehle¹,

Iorga²,

Pfitzer³

2007

American Journal of Physiology-Regulatory, Integrative and Comp

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CA 2ϩ SENSITIVITY OF STRIATED muscle contraction is modulated by a number of factors, the mechanism by which force is altered by Ca 2ϩ appears to be complex. If we focus on the level of the regulatory, heterotrimeric troponin complex (Tn ϭ TnC⅐TnI⅐TnT), not only an altered Ca 2ϩ affinity of troponin C (TnC) but also developmental changes in troponin I (TnI) isoforms manifest themselves in altered Ca 2ϩ sensitivity. For example, neonatal hearts, which express the slow skeletal TnI (ssTnI), exhibit an increased Ca 2ϩ sensitivity compared with adult hearts containing the cardiac TnI (cTnI) isoform (19,21,28).In this issue of AJP-Regulatory, Integrative and Comparative Physiology, the article "Myofilament calcium sensitivity does not affect cross-bridge activation-relaxation kinetics" by de Tombe and coworkers (6) investigated whether specific interventions on TnC and TnI leading to Ca 2ϩ sensitization of contraction affect force kinetics in myofibrils. To alter the regulatory function of Tn, they used two straightforward approaches: 1) treatment of the myofibrils with bepridil, a Ca 2ϩ sensitizer known to specifically bind to TnC; and 2) replacement of the endogeneous, fast skeletal Tn (fsTn) in the rabbit psoas myofibril by either cTnC ⅐ cTnI ⅐ cTnT or cTnC⅐ssTnI⅐cTnT. Bepridil and both types of Tn replacements increased the Ca 2ϩ sensitivity (pCa 50 ) of myofibrillar force generation, whereby ssTnI increased it more than cTnI, in agreement with studies on skinned fibers (21,36). Under all conditions, the authors find that Ca 2ϩ activation induces a monoexponential rise of force with a rate constant k act . Yet, importantly, de Tombe et al. (6) found that none of these interventions altered the maximum Ca 2ϩ -activated force nor produced a different k act -force relationship, i.e., for a given active force, the observed kinetics of contraction were similar. Even more intriguingly, neither Tn exchange nor bepridil caused any significant alterations in the kinetics of force decay following rapid Ca 2ϩ removal; no slowing down of mechanical relaxation was observed as one might have expected from the elevated Ca 2ϩ sensitivity induced by these interventions. We learn from these results that the nature of Tn defines the Ca 2ϩ sensitivity of contraction, while it does not influence the kinetics of myofibrillar contraction and relaxation, provided that the complex is able to completely turn off and fully turn on.To better understand the implications of these results, in terms of the kinetic mechanism of Ca 2ϩ -induced contraction, one has to consider why the rate constant of force development is Ca 2ϩ dependent at all. This feature was first approached by Brenner (2) by investigating the Ca 2ϩ dependence of the rate constant of force redevelopment (k tr ) to demonstrate that Ca 2ϩ regulation of force generation results from the gradual increase in the apparent turnover rate constant (f app ) by which crossbridges enter force-generating states. This was inconsistent with the hypothesis that Ca 2ϩ -dependent thin-filament...

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Steric-model for activation of muscle thin filaments

Cited by 440 publications

References 31 publications

Identification of a contractile deficit in adult cardiac myocytes expressing hypertrophic cardiomyopathy–associated mutant troponin T proteins

Identification of a contractile deficit in adult cardiac myocytes expressing hypertrophic cardiomyopathy–associated mutant troponin T proteins

Cooperative Effect of Calcium Binding to Adjacent Troponin Molecules on the Thin Filament-Myosin Subfragment 1 MgATPase Rate

Calcium regulation of troponin and its role in the dynamics of contraction and relaxation

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