Ca<sup>2+</sup> Binding to Cardiac Troponin C in the Myofilament Lattice and Its Relation to the Myofibrillar ATPase Activity

Morimoto, Sachio; Ohtsuki, Iwao

doi:10.1111/j.1432-1033.1994.tb20085.x

Cited by 18 publications

(17 citation statements)

References 39 publications

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“…This raises the possibility that the increased buffering is a property of the endogenous Ca 21 buffer(s). Since most EF-hand Ca 21 binding proteins have four Ca 21 binding sites and cooperativity has been observed in several cases, including troponin-C (Iida, 1988;Morimoto and Ohtsuki, 1994;Teleman et al, 1983), calmodulin (Olwin and Storm, 1985), and calbindin (Leathers et al, 1990), we thought that positive cooperativity might achieve the observed result. For the simulations shown in Fig.…”

Section: A Virtual Cell To Explain Dynamic Ca 21 Redistributions Durimentioning

confidence: 90%

“…7, B and C). The rationale for this was that most EF-hand Ca 21 binding proteins have four Ca 21 binding sites, and cooperativity has been observed in several cases (Iida, 1988;Leathers et al, 1990;Morimoto and Ohtsuki, 1994;Olwin and Storm, 1985;Teleman et al, 1983). However, we stress that these changes were introduced so that our simulations better reproduced the measured fluorescence changes in the cytosol and not because we have any experimental evidence that the endogenous Ca 21 binding protein in adrenal chromaffin cells has four Ca 21 binding sites or exhibits positive cooperativity.…”

Section: Ca 21 Clearance and Decay Of Ca 21 Signalsmentioning

confidence: 95%

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Spatial Distribution of Ca2+ Signals during Repetitive Depolarizing Stimuli in Adrenal Chromaffin Cells

Marengo

Monck

2003

Biophysical Journal

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Exocytosis in adrenal chromaffin cells is strongly influenced by the pattern of stimulation. To understand the dynamic and spatial properties of the underlying Ca(2+) signal, we used pulsed laser Ca(2+) imaging to capture Ca(2+) gradients during stimulation by single and repetitive depolarizing stimuli. Short single pulses (10-100 ms) lead to the development of submembrane Ca(2+) gradients, as previously described (F. D. Marengo and J. R. Monck, 2000, Biophysical Journal, 79:1800-1820). Repetitive stimulation with trains of multiple pulses (50 ms each, 2Hz) produce a pattern of intracellular Ca(2+) increase that progressively changes from the typical Ca(2+) gradient seen after a single pulse to a Ca(2+) increase throughout the cell that peaks at values 3-4 times higher than the maximum values obtained at the end of single pulses. After seven or more pulses, the fluorescence increase was typically larger in the interior of the cell than in the submembrane region. The pattern of Ca(2+) gradient was not modified by inhibitors of Ca(2+)-induced Ca(2+) release (ryanodine), inhibitors of IP(3)-induced Ca(2+) release (xestospongin), or treatments designed to deplete intracellular Ca(2+) stores (thapsigargin). However, we found that the large fluorescence increase in the cell interior spatially colocalized with the nucleus. These results can be simulated using mathematical models of Ca(2+) redistribution in which the nucleus takes up Ca(2+) by active or passive transport mechanisms. These results show that chromaffin cells can respond to depolarizing stimuli with different dynamic Ca(2+) signals in the submembrane space, the cytosol, and the nucleus.

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Section: A Virtual Cell To Explain Dynamic Ca 21 Redistributions Durimentioning

confidence: 90%

Section: Ca 21 Clearance and Decay Of Ca 21 Signalsmentioning

confidence: 95%

Spatial Distribution of Ca2+ Signals during Repetitive Depolarizing Stimuli in Adrenal Chromaffin Cells

Marengo

Monck

2003

Biophysical Journal

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“…The molecular mechanisms of this SLdependent effect are currently debated but thought to result, at least in part, from changes in lattice spacing between the thin and thick filaments, and/or changes in myosin crossbridge orientation that increase the probability of myosin binding to actin at longer SLs (9,11,17,20,25,41,42). Furthermore, crossbridge binding enhances Ca 2ϩ binding to troponin (cTn) in cardiac muscle, a unique form of cooperative thin filament activation whose mechanism is currently not well understood (10,11,19,32). The net result of these interactions is an apparent increase in Ca 2ϩ sensitivity of thin filament activation at longer SLs, whereby a given submaximal Ca 2ϩ concentration ([Ca 2ϩ ]) results in greater contractile force development.…”

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confidence: 98%

Enhanced Ca²⁺ binding of cardiac troponin reduces sarcomere length dependence of contractile activation independently of strong crossbridges

Korte

Feest

Razumova

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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Calcium sensitivity of the force-pCa relationship depends strongly on sarcomere length (SL) in cardiac muscle and is considered to be the cellular basis of the Frank-Starling law of the heart. SL dependence may involve changes in myofilament lattice spacing and/or myosin crossbridge orientation to increase probability of binding to actin at longer SLs. We used the L48Q cardiac troponin C (cTnC) variant, which has enhanced Ca(2+) binding affinity, to test the hypotheses that the intrinsic properties of cTnC are important in determining 1) thin filament binding site availability and responsiveness to crossbridge activation and 2) SL dependence of force in cardiac muscle. Trabeculae containing L48Q cTnC-cTn lost SL dependence of the Ca(2+) sensitivity of force. This occurred despite maintaining the typical SL-dependent changes in maximal force (F(max)). Osmotic compression of preparations at SL 2.0 μm with 3% dextran increased F(max) but not pCa(50) in L48Q cTnC-cTn exchanged trabeculae, whereas wild-type (WT)-cTnC-cTn exchanged trabeculae exhibited increases in both F(max) and pCa(50). Furthermore, crossbridge inhibition with 2,3-butanedione monoxime at SL 2.3 μm decreased F(max) and pCa(50) in WT cTnC-cTn trabeculae to levels measured at SL 2.0 μm, whereas only F(max) was decreased with L48Q cTnC-cTn. Overall, these results suggest that L48Q cTnC confers reduced crossbridge dependence of thin filament activation in cardiac muscle and that changes in the Ca(2+) sensitivity of force in response to changes in SL are at least partially dependent on properties of thin filament troponin.

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“…On Ca 2ϩ binding to TnC, a Ca 2ϩ -induced interaction of TnC with TnI relieves the inhibitory action of TnI exerted on the thin filament and enables the myosin head to cyclically interact with actin in the thin filament and generate force. The Ca 2ϩ sensitivity of muscle contraction is determined by the Ca 2ϩ -binding affinity of TnC, which is dynamically altered through interaction with TnI and TnT in the myofilament lattice (3)(4)(5)(6)(7)(8).…”

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confidence: 99%

Ca ²⁺ -desensitizing effect of a deletion mutation ΔK210 in cardiac troponin T that causes familial dilated cardiomyopathy

Morimoto

Harada

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

150

114

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A deletion mutation ⌬K210 in cardiac troponin T (cTnT) was recently found to cause familial dilated cardiomyopathy (DCM). To explore the effect of this mutation on cardiac muscle contraction under physiological conditions, we determined the Ca 2؉ -activated force generation in permeabilized rabbit cardiac muscle fibers into which the mutant and wild-type cTnTs were incorporated by using our TnT exchange technique. The free Ca 2؉ concentrations required for the force generation were higher in the mutant cTnTexchanged fibers than in the wild-type cTnT-exchanged ones, with no statistically significant differences in maximal force-generating capability and cooperativity. Exchanging the mutant cTnT into isolated cardiac myofibrils also increased the free Ca 2؉ concentrations required for the activation of ATPase. In contrast, a deletion mutation ⌬E160 in cTnT that causes familial hypertrophic cardiomyopathy (HCM) decreased the free Ca 2؉ concentrations required for force generation, just as in the case of the other HCM-causing mutations in cTnT. The results indicate that cTnT mutations found in the two distinct forms of cardiomyopathy (i.e., HCM and DCM) change the Ca 2؉ sensitivity of cardiac muscle contraction in opposite directions. The present study strongly suggests that Ca 2؉ desensitization of force generation in sarcomere is a primary mechanism for the pathogenesis of DCM associated with the deletion mutation ⌬K210 in cTnT.C ontraction of the vertebrate-striated muscles (i.e., skeletal and cardiac muscles) is regulated by Ca 2ϩ through its binding to a specific regulatory protein complex, troponin (Tn), which is distributed at regular intervals along the entire thin filament (1, 2). Tn is a complex of three different proteins, troponin T (TnT; tropomyosin-binding component), troponin I (TnI; inhibitory component), and troponin C (TnC; Ca 2ϩ -binding component). On Ca 2ϩ binding to TnC, a Ca 2ϩ -induced interaction of TnC with TnI relieves the inhibitory action of TnI exerted on the thin filament and enables the myosin head to cyclically interact with actin in the thin filament and generate force. The Ca 2ϩ sensitivity of muscle contraction is determined by the Ca 2ϩ -binding affinity of TnC, which is dynamically altered through interaction with TnI and TnT in the myofilament lattice (3-8).Mutations in genes for cardiac troponin T (cTnT) and cardiac troponin I (cTnI) have been found to cause familial hypertrophic cardiomyopathy (HCM), an autosomal dominant heart disease characterized by asymmetrical ventricular hypertrophy with a high incidence of sudden death in young adults (9). We have already examined the effects of eight HCM-linked cTnT mutations (I79N, R92Q, ⌬E160, E244D, R278C, and two truncated mutants produced by a splice donor site mutation Int15G 1 3A) and six HCM-linked cTnI mutations (R145G, R145Q, R162W, ⌬K183, G203S, and K206Q) on the contractile functions of cardiac muscle by using a technique for exchanging the exogenous Tn complex into skinned muscle fibers and isolated myofibrils. We found t...

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Ca²⁺ Binding to Cardiac Troponin C in the Myofilament Lattice and Its Relation to the Myofibrillar ATPase Activity

Cited by 18 publications

References 39 publications

Spatial Distribution of Ca2+ Signals during Repetitive Depolarizing Stimuli in Adrenal Chromaffin Cells

Spatial Distribution of Ca2+ Signals during Repetitive Depolarizing Stimuli in Adrenal Chromaffin Cells

Enhanced Ca²⁺ binding of cardiac troponin reduces sarcomere length dependence of contractile activation independently of strong crossbridges

Ca ²⁺ -desensitizing effect of a deletion mutation ΔK210 in cardiac troponin T that causes familial dilated cardiomyopathy

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Ca2+ Binding to Cardiac Troponin C in the Myofilament Lattice and Its Relation to the Myofibrillar ATPase Activity

Cited by 18 publications

References 39 publications

Spatial Distribution of Ca2+ Signals during Repetitive Depolarizing Stimuli in Adrenal Chromaffin Cells

Spatial Distribution of Ca2+ Signals during Repetitive Depolarizing Stimuli in Adrenal Chromaffin Cells

Enhanced Ca2+ binding of cardiac troponin reduces sarcomere length dependence of contractile activation independently of strong crossbridges

Ca 2+ -desensitizing effect of a deletion mutation ΔK210 in cardiac troponin T that causes familial dilated cardiomyopathy

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Resources

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Ca²⁺ Binding to Cardiac Troponin C in the Myofilament Lattice and Its Relation to the Myofibrillar ATPase Activity

Enhanced Ca²⁺ binding of cardiac troponin reduces sarcomere length dependence of contractile activation independently of strong crossbridges

Ca ²⁺ -desensitizing effect of a deletion mutation ΔK210 in cardiac troponin T that causes familial dilated cardiomyopathy