Identification of a Region of Troponin I Important in Signaling Cross-bridge-dependent Activation of Cardiac Myofilaments

Engel, Patti L.; Kobayashi, Tomoyoshi; Biesiadecki, Brandon J.; Davis, Jonathan P.; Tikunova, Svetlana B.; Wu, Steven C.; Solaro, R. John

doi:10.1074/jbc.m512337200

Cited by 24 publications

(28 citation statements)

References 53 publications

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“…30 Furthermore, we have reported that the cTnI N-terminal region surrounding Ala66, a region that strongly interacts with the cTnC C-lobe, is a significant locus of signaling in the activation of the thin filament by strongly bound cross-bridges. 31 Together with these previous findings, our current results provide further evidence indicating a unique role for the cTnC C-lobe interaction with the cTnI N terminus in myofilament contractile regulation.…”

Section: Discussionsupporting

confidence: 72%

The Troponin C G159D Mutation Blunts Myofilament Desensitization Induced by Troponin I Ser23/24 Phosphorylation

Biesiadecki

Kobayashi

Walker

et al. 2007

Circulation Research

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113

131

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Abstract-Striated muscle contraction is regulated by the binding of Ca 2ϩ to the N-terminal regulatory lobe of the cardiac troponin C (cTnC) subunit in the troponin complex. In the heart, ␤-adrenergic stimulation induces protein kinase A phosphorylation of cardiac troponin I (cTnI) at Ser23/24 to alter the interaction of cTnI with cTnC in the troponin complex and is critical to the regulation of cardiac contractility. We investigated the effect of the dilated cardiomyopathy linked cTnC Gly159 to Asp (cTnC-G159D) mutation on the development of Ca 2ϩ -dependent tension and ATPase rate in whole troponin-exchanged skinned rat trabeculae. Even though this mutation is located in the C-terminal lobe of cTnC, the G159D mutation was demonstrated to depress ATPase activation and filament sliding in vitro. The effects of this mutation within the cardiac myofilament are unknown. Our results demonstrate that the cTnC-G159D mutation by itself does not alter the myofilament response to Ca 2ϩ in the cardiac muscle lattice. However, in the presence of cTnI phosphorylated at Ser23/24, which reduced Ca 2ϩ sensitivity and enhanced cross-bridge cycling in controls, cTnC-G159D specifically blunted the phosphorylation induced decrease in Ca 2ϩ -sensitive tension development without altering cross-bridge cycling. Measurements in purified troponin confirmed that this cTnC-G159D blunting of myofilament desensitization results from altered Ca 2ϩ -binding to cTnC. Our results provide novel evidence that modification of the cTnC-cTnI interaction has distinct effects on troponin Ca 2ϩ -binding and cross-bridge kinetics to suggest a novel role for thin filament mutations in the modulation of myofilament function through ␤-adrenergic signaling as well as the development of cardiomyopathy.

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Section: Discussionsupporting

confidence: 72%

The Troponin C G159D Mutation Blunts Myofilament Desensitization Induced by Troponin I Ser23/24 Phosphorylation

Biesiadecki

Kobayashi

Walker

et al. 2007

Circulation Research

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113

131

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“…However, the relative orientation of the ITarm to actin filament axis is more sensitive to strong cross-bridge attachment than to Ca 2+ -binding to the regulatory sites [41]. Moreover, recent data indicate that the IT-arm region is involved in the cross-bridge dependent activation of myofilaments [21]. These studies demonstrated that a region of cTnI in the near N-terminal region (surrounding Ala-65), which interacts with C-terminal regions of cTnC and cTnT, is of particular significance in transducing signaling of thin filament activation by strong cross-bridges.…”

Section: Molecular Mechanisms Of Ctni Function In Ca2+ and Crossbridgmentioning

confidence: 99%

“…Apart from their significant effects on cardiac dynamics, cTnI phosphorylation at the PKA sites affects length dependence of activation (LDA) [20]. Cooperative mechanisms involving feedback effects of strongly bound cross-bridges are important for LDA and are also sensitive to isoform specific structure in cardiac TnI [21].…”

Section: Specific Modifications In Troponin I Affect the Dynamics Andmentioning

confidence: 99%

The unique functions of cardiac troponin I in the control of cardiac muscle contraction and relaxation

Solaro

Rosevear

Kobayashi

2008

Biochemical and Biophysical Research Communications

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119

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We review development of evidence and current perceptions of the multiple and significant functions of cardiac troponin I in regulation and modulation of cardiac function. Our emphasis is on the unique structure function relations of the cardiac isoform of troponin I, especially regions containing sites of phosphorylation. The data indicate that modifications of specific regions cardiac troponin I by phosphorylations either promote or reduce cardiac contractility. Thus, a homeostatic balance in these phosphorylations is an important aspect of control of cardiac function. A new concept is the idea that the homeostatic mechanisms may involve modifications of intra-molecular interactions in cardiac troponin I. KeywordsCardiac; Sarcomeres; Adrenergic stimulation; Mechanics; Kinases; Phosphatases In the time since the troponin discovery and naming by the laboratory of Setsuro Ebashi [1], there has been a constant stream of evidence indicating the substantial role of modifications in cardiac troponin (cTn) as a critical control element in the body's response to physiological stressors such as the hemodynamic demands of exercise. It is now widely recognized that regulatory processes at the level of the sarcomeres and the hetero-trimeric Tn complex involve not only the reception of Ca 2+ by cTnC, but also transduction of this Ca-binding signal by cTnI and cTnT [2,3]. Multiple interactions of cTnI and cTnT with actin and tropomyosin (Tm) control the number and kinetics of interactions of cross-bridges with the thin filament. Our focus here on cTnI serves to highlight the significant impact of modifications in the function of Tn in working cardiac myocytes and in the integrated physiological responses to exercise, which we have reviewed previously [4,5]. Evidence summarized below indicates that phosphorylation of cTnI by adrenergic signaling cascades is an indispensable control mechanism in matching cardiac output to venous return and myocyte dynamics to heart rate. Specific modifications in troponin I affect the dynamics and intensity of the heart beatElucidation of the function of an N-terminal extension of ~30 amino acids with sites (Ser-23, Ser-24) of phosphorylation by protein kinase A (PKA), not present in the fast skeletal (fsTnI) or slow skeletal isoforms (ssTnI), provided the first evidence that cTnI may have a special role * Corresponding

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“…At low [Ca 2ϩ ], the Ca 2ϩ -regulated on rate of cTn becomes negligible, and the overall dynamics of the thin filament (k on ϩ k off ) among off and on states become slowest, i.e., just determined by k off (7). Troponin containing ssTnI has been shown to have a three times slower rate of Ca 2ϩ dissociation from TnC (k off ) compared with troponin containing cTnI (8). This is in agreement with the enhanced Ca 2ϩ sensitivity of myofibrils containing ssTnI, compared to myofibrils containing cTnI found by de Tombe et al (6).…”

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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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Identification of a Region of Troponin I Important in Signaling Cross-bridge-dependent Activation of Cardiac Myofilaments

Cited by 24 publications

References 53 publications

The Troponin C G159D Mutation Blunts Myofilament Desensitization Induced by Troponin I Ser23/24 Phosphorylation

The Troponin C G159D Mutation Blunts Myofilament Desensitization Induced by Troponin I Ser23/24 Phosphorylation

The unique functions of cardiac troponin I in the control of cardiac muscle contraction and relaxation

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

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