Molecular and functional consequences of mutations in the central helix of cardiac troponin C

Swindle, Nicholas; Albury, Acchia; Baroud, Belal; Burney, Maryam; Tikunova, Svetlana B.

doi:10.1016/j.abb.2014.03.004

Cited by 7 publications

(9 citation statements)

References 57 publications

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“…It is also likely that G159C-cTnC does not properly bind other thin ilament proteins, actin, cTnT or tropomyosin. Similar results were found by Swindle, et al [30].…”

Section: A Mutation Ctnc Giving Unexpectedly Dcm Although Loss Of Ca supporting

confidence: 92%

The mechanisms of cardiac myopathies, a kinetics approach: Leading review

Smith¹

2020

J Cardiol Cardiovasc Med

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“…It is also likely that G159C-cTnC does not properly bind other thin ilament proteins, actin, cTnT or tropomyosin. Similar results were found by Swindle, et al [30].…”

Section: A Mutation Ctnc Giving Unexpectedly Dcm Although Loss Of Ca supporting

confidence: 92%

The mechanisms of cardiac myopathies, a kinetics approach: Leading review

Smith¹

2020

J Cardiol Cardiovasc Med

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“…The cTnC D73N and cTnI S22D/S23D mutants were generated as previously described and verified by DNA sequencing (Tikunova et al, 2010 ). The cTn complex subunits were expressed, purified, and quantified as previously described (Albury et al, 2012 ; Swindle et al, 2014 ). Rabbit fast skeletal actin and bovine cTm were a generous gift from Dr. Darl Swartz (Delaware Valley College, Doylestown, PA).…”

Section: Methodsmentioning

confidence: 99%

“…The cTn complexes and thin filaments were prepared and reconstituted as previously described (Albury et al, 2012 ; Swindle et al, 2014 ).…”

Section: Methodsmentioning

confidence: 99%

“…Steady-state fluorescence measurements were carried out using a Perkin-Elmer LS55 fluorescence spectrometer at 15°C, as previously described (Albury et al, 2012 ; Swindle et al, 2014 ). Data were fit with a logistic sigmoid function mathematically equivalent to the Hill equation.…”

Section: Methodsmentioning

confidence: 99%

“…Data represent a mean of at least three titrations ± S.E. All kinetic measurements were performed using an Applied Photophysics Ltd. (Leatherhead, UK) model SX.18MV stopped-flow instrument with a dead time of ~1.4 ms at 15°C, as previously described (Albury et al, 2012 ; Swindle et al, 2014 ). Data represent an average of at least three separate experiments ± S.E., each averaging at least five traces fit with a single exponential equation.…”

Section: Methodsmentioning

confidence: 99%

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Knock-in mice harboring a Ca2+ desensitizing mutation in cardiac troponin C develop early onset dilated cardiomyopathy

et al. 2015

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Citation:McConnell BK, Singh S, Fan Q, Hernandez A, Portillo JP, Reiser PJ and Tikunova SB (2015) Knock-in mice harboring a Ca 2+ desensitizing mutation in cardiac troponin C develop early onset dilated cardiomyopathy. Front. Physiol. 6:242. doi: 10.3389/fphys.2015.00242 Knock-in mice harboring a Ca 2+ desensitizing mutation in cardiac troponin C develop early onset dilated cardiomyopathy The physiological consequences of aberrant Ca 2+ binding and exchange with cardiac myofilaments are not clearly understood. In order to examine the effect of decreasing Ca 2+ sensitivity of cTnC on cardiac function, we generated knock-in mice carrying a D73N mutation (not known to be associated with heart disease in human patients) in cTnC. The D73N mutation was engineered into the regulatory N-domain of cTnC in order to reduce Ca 2+ sensitivity of reconstituted thin filaments by increasing the rate of Ca 2+ dissociation. In addition, the D73N mutation drastically blunted the extent of Ca 2+ desensitization of reconstituted thin filaments induced by cTnI pseudo-phosphorylation. Compared to wild-type mice, heterozygous knock-in mice carrying the D73N mutation exhibited a substantially decreased Ca 2+ sensitivity of force development in skinned ventricular trabeculae. Kaplan-Meier survival analysis revealed that median survival time for knock-in mice was 12 weeks. Echocardiographic analysis revealed that knock-in mice exhibited increased left ventricular dimensions with thinner walls. Echocardiographic analysis also revealed that measures of systolic function, such as ejection fraction (EF) and fractional shortening (FS), were dramatically reduced in knock-in mice. In addition, knock-in mice displayed electrophysiological abnormalities, namely prolonged QRS and QT intervals. Furthermore, ventricular myocytes isolated from knock-in mice did not respond to β-adrenergic stimulation. Thus, knock-in mice developed pathological features similar to those observed in human patients with dilated cardiomyopathy (DCM). In conclusion, our results suggest that decreasing Ca 2+ sensitivity of the regulatory N-domain of cTnC is sufficient to trigger the development of DCM.

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Structure and function of cardiac troponin C (TNNC1): Implications for heart failure, cardiomyopathies, and troponin modulating drugs

Hwang

2015

Gene

112

105

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In striated muscle, the protein troponin complex turns contraction on and off in a calcium-dependent manner. The calcium-sensing component of the complex is troponin C, which is expressed from the TNNC1 gene in both cardiac muscle and slow-twitch skeletal muscle (identical transcript in both tissues) and the TNNC2 gene in fast-twitch skeletal muscle. Cardiac troponin C (cTnC) is made up of two globular EF-hand domains connected by a flexible linker. The structural C-domain (cCTnC) contains two high affinity calcium-binding sites that are always occupied by Ca2+ or Mg2+ under physiologic conditions, stabilizing an open conformation that remains anchored to the rest of the troponin complex. In contrast, the regulatory N-domain (cNTnC) contains a single low affinity site that is largely unoccupied at resting calcium concentrations. During muscle activation, calcium binding to cNTnC favors an open conformation that binds to the switch region of troponin I, removing adjacent inhibitory regions of troponin I from actin and allowing muscle contraction to proceed. Regulation of the calcium binding affinity of cNTnC is physiologically important, because it directly impacts the calcium sensitivity of muscle contraction. Calcium sensitivity can be modified by drugs that stabilize the open form of cNTnC, post-translational modifications like phosphorylation of troponin I, or downstream thin filament protein interactions that impact the availability of the troponin I switch region. Recently, mutations in cTnC have been associated with hypertrophic or dilated cardiomyopathy. A detailed understanding of how calcium sensitivity is regulated through the troponin complex is necessary for explaining how mutations perturb its function to promote cardiomyopathy and how post-translational modifications in the thin filament affect heart function and heart failure. Troponin modulating drugs are being developed for the treatment of cardiomyopathies and heart failure.

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Molecular and functional consequences of mutations in the central helix of cardiac troponin C

Cited by 7 publications

References 57 publications

The mechanisms of cardiac myopathies, a kinetics approach: Leading review

The mechanisms of cardiac myopathies, a kinetics approach: Leading review

Knock-in mice harboring a Ca2+ desensitizing mutation in cardiac troponin C develop early onset dilated cardiomyopathy

Structure and function of cardiac troponin C (TNNC1): Implications for heart failure, cardiomyopathies, and troponin modulating drugs

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