Troponin I serines 43/45 and regulation of cardiac myofilament function.

  title={Troponin I serines 43/45 and regulation of cardiac myofilament function.},
  author={W. Glen Pyle and Marius P. Sumandea and R. John Solaro and Pieter P de Tombe},
  journal={American journal of physiology. Heart and circulatory physiology},
  volume={283 3},
We studied Ca(2+) dependence of tension and actomyosin ATPase rate in detergent extracted fiber bundles isolated from transgenic mice (TG), in which cardiac troponin I (cTnI) serines 43 and 45 were mutated to alanines (cTnI S43A/S45A). Basal phosphorylation levels of cTnI were lower in TG than in wild-type (WT) mice, but phosphorylation of cardiac troponin T was increased. Compared with WT, TG fiber bundles showed a 13% decrease in maximum tension and a 20% increase in maximum MgATPase activity… 

Figures and Tables from this paper

Myofilament incorporation and contractile function after gene transfer of cardiac troponin I Ser43/45Ala.

Regulation of cardiac contractile function by troponin I phosphorylation.

Effects of Protein Kinase C Phosphorylation of Cardiac Troponin I:An Experimental and Model-Based Study

A modest increase in PKC-induced cTnI phosphorylation can significantly regulate cardiac muscle contraction and negative inotropy via decreased crossbridge formation and negative lusitropy via persistence of myofilament active state is revealed.

Troponin I protein kinase C phosphorylation sites and ventricular function.

Phosphorylation or Glutamic Acid Substitution at Protein Kinase C Sites on Cardiac Troponin I Differentially Depress Myofilament Tension and Shortening Velocity*

Novel site specificity of effects of PKC phosphorylation on cTnI function is demonstrated and the complexity of modulation of the actin-myosin interaction by specific changes in the thin filament is emphasized.

Augmented Protein Kinase C-α–Induced Myofilament Protein Phosphorylation Contributes to Myofilament Dysfunction in Experimental Congestive Heart Failure

The results suggest that in end-stage congestive heart failure, the myofilament proteins exist in a hyperphosphorylated state attributable, in part, to increased activity and signaling of PKC-α.

Left Ventricular and Myocardial Function in Mice Expressing Constitutively Pseudophosphorylated Cardiac Troponin I

A modest increase in PKC-induced cTnI phosphorylation can significantly alter cardiac muscle contraction: negative inotropy via decreased cross-bridge formation and negative lusitropy via persistence of myofilament active state.

Molecular and Integrated Biology of Thin Filament Protein Phosphorylation in Heart Muscle

The main sites for PKC‐dependent phosphorylation on cTnI are Ser43, Ser45, and Thr144 and oncTnT are Thr197, Ser201, Thr206 and Thr287 (mouse sequence), and the recent data on the specific functional role of PKC phosphorylations are summarized.

Protein Kinase C&egr; Overexpression Alters Myofilament Properties and Composition During the Progression of Heart Failure

Characterization of a transgenic mouse that overexpresses constitutively active protein kinase C&egr; in the heart and slowly develops a dilated cardiomyopathy with failure is reported to implicate the disruption of the myofibrillar proteins and their interactions in the propagation of dilated cardiac disease.

Contractile Function of the Human Myocardium: Impact of Troponin Phosphorylation

Specific PKC α‐mediated phosphorylation of cTn increases myofilament Ca‐sensitivity and decreases maximal force and Phosphorylation at the newly identified PKC sites in human troponin may contribute to the intricate effects of PKCα on my ofilament function.



alpha-Adrenergic response and myofilament activity in mouse hearts lacking PKC phosphorylation sites on cardiac TnI.

Evidence is provided that specific PKC-mediated phosphorylation of Ser(43) and Ser(45) of cTnI plays an important role in regulating force development in the intact myocardium.

Transgenic incorporation of skeletal TnT into cardiac myofilaments blunts PKC-mediated depression of force.

The data suggest that fast skeletal TnT may play an important role in amplifying the myofilament depression induced by PKC-mediated phosphorylation of cTnI, and that cTNT may also play a role in increasing Ca(2+) sensitivity in skinned fiber bundles from transgenic mouse hearts.

Differential sensitivity to isoprenaline of troponin I and phospholamban phosphorylation in isolated rat hearts.

The data indicate a functional compartmentalization of the cAMP signal cascade and confirm that phosphorylation of TNI rather than of PLB is related to changes in mechanical myocardial responses.

PKC translocation without changes in Gαq and PLC-β protein abundance in cardiac hypertrophy and failure.

Differential PKC activation may be mediated by increases in Gαq and PLC-βI activity rather than upregulation of expression, andTranslocation of PKC-α, -ε, and -γ from cytosolic to membranous fractions were significantly increased during POH and CHF.

Arachidonic acid-dependent phosphorylation of troponin I and myosin light chain 2 in cardiac myocytes.

It is demonstrated that Ca2+ transients in populations of fura 2-loaded myocytes were potentiated by AA and ET via activation of protein kinase C, and the ability of these agonists to stimulate phosphorylation of TnI or MLC2 did not require extracellular Ca2- or intact intracellularCa2+ stores.

Cardiac Troponin I Mutants

It is suggested that Ser-43/Ser-45 and Ser-23/ Ser-24 in cardiac TnI are important for normal Ca2+ sensitivity of the myofilament, and that phosphorylation of Ser- 43/Ser -45 andSer-23-24 is primarily involved in the protein kinase C regulation of the activity and Ca2 + sensitivity, respectively, of actomyosin S-1 MgATPase.

Troponin I phosphorylation in heart homogenate from diabetic rat.

Troponin I phosphorylation in the normal and failing adult human heart.

It is confirmed that the adult human heart expresses only cTnI, and this phosphorylation difference could underlie the reported greater myofibrillar calcium sensitivity of failing myocardium.

Effect of endothelin-1 on actomyosin ATPase activity. Implications for the efficiency of contraction.

The results indicate that the effects of endothelin-1 on the force of contraction and the rate of ATP hydrolysis are not tightly coupled and are changed in the opposite directions by endothelins-1 over most of its effective dose-range, raising the possibility that endotheli-1 may increase the economy of contraction.

Differential regulation of cardiac actomyosin S-1 MgATPase by protein kinase C isozyme-specific phosphorylation of specific sites in cardiac troponin I and its phosphorylation site mutants.

It is demonstrated, for the first time, that distinct functional consequences could arise from the site-selective preferences of PKC-alpha and -delta for phosphorylating a single substrate in the myocardium, i.e., TnI.