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Tnni3  -  troponin I type 3 (cardiac)

Rattus norvegicus

Synonyms: Cardiac troponin I, Ctni, TnI, Tni, Troponin I, cardiac muscle, ...
 
 
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Disease relevance of Tnni3

  • The myofilament protein troponin I (TnI) has a key isoform-dependent role in the development of contractile failure during acidosis and ischemia [1].
  • In parallel experiments, skinned trabeculae were treated with calpain I for 20 minutes; Western blots showed a TnI degradation pattern similar to that observed in stunned myocardium [2].
  • Selective troponin I (TnI) modification has been demonstrated to be in part responsible for the contractile dysfunction observed with myocardial ischemia/reperfusion injury [3].
  • The results show that phosphorylation of troponin I (TnI) was increased by 268% during the early phase (9 h after CLP) but decreased by 46% during the late phase (18 h after CLP) of sepsis [4].
  • CONCLUSIONS: The studies provide firm evidence that both TnC and TnI moieties are involved in the mechanism of acidosis causing reduction in the Ca sensitivity of force development in the myocardium [5].
 

High impact information on Tnni3

  • This pH-sensitive 'histidine button' engineered in TnI produces a titratable molecular switch that 'senses' changes in the intracellular milieu of the cardiac myocyte and responds by preferentially augmenting acute and long-term function under pathophysiological conditions [1].
  • Here we show that cardiac performance in vitro and in vivo is enhanced when a single histidine residue present in the fetal cardiac TnI isoform is substituted into the adult cardiac TnI isoform at codon 164 [1].
  • Adenoviral-mediated gene transfer of epitope-tagged tropomyosin (Tm) and troponin I (TnI) into adult cardiac myocytes in vitro along with confocal microscopy was used to examine the incorporation of these newly synthesized proteins into myofilaments of a fully differentiated contractile cell [6].
  • Interestingly, while TnI was first detected in cardiac sarcomeres along the entire length of the thin filament, the epitope-tagged Tm preferentially replaced Tm at the pointed end of the thin filament [6].
  • TnI degradation could be blocked by preventing the activation of endogenous calpains with 25 micromol/L calpeptin (4.3 +/- 0.6%) [7].
 

Chemical compound and disease context of Tnni3

 

Biological context of Tnni3

  • The amino acid sequence of rat cardiac TnI is highly similar to that of other mammalian species in the portion of the molecule (residues 33-210) that is also homologous to skeletal muscle TnI isoforms [10].
  • In parallel, TnI phosphorylation was increased 5-fold in cardiocytes isolated from the hearts of diabetic animals relative to control animals (P < .01) [11].
  • The inhibition due to phosphorylated TnI was partially overcome as the concentration of myosin or S-1 increased, suggesting simple competition of phosphorylated TnI with myosin or S-1 for actin binding sites [12].
  • Comparative analysis suggests that cardiac TnI exon 1 corresponds to fast TnI exons 1 and 2 and that cardiac exon 3, which codes for most of the cardiac-specific amino-terminal extension and has no counterpart in the fast gene, evolved by exon insertion/deletion [13].
  • Full activation of the Ca(2+) regulatory switch (CRS) requires two switching steps in cTnI: binding of the TnI regulatory region to hydrophobic sites in the N-domain of Ca(2+)-bound troponin C and release of the adjacent TnI-I from actin [14].
 

Anatomical context of Tnni3

  • Cardiac TnI mRNA is weakly expressed in the 18-day fetal heart and accumulates in neonatal and postnatal stages [10].
  • Since PKC phosphorylation of TnI has been associated with a loss of calcium sensitivity of intact myofibrils, these data suggest that angiotensin II receptor-mediated activation of PKC may play a role in the contractile dysfunction seen in chronic diabetes [11].
  • Based on these results, acceleration of myocyte relaxation during protein kinase C activation largely depended on cardiac troponin-I phosphorylation [15].
  • The present study has 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 [16].
  • BACKGROUND: Troponin I (TnI) and myosin light chain 2 (MLC2) are important myofibrillar proteins involved in the regulation of myofilament calcium (Ca2+) sensitivity and cardiac inotropy [17].
 

Associations of Tnni3 with chemical compounds

  • Incubation with either PMA, AA, or ET resulted in similar increases in 32Pi incorporation into troponin I (TnI) and myosin light chain 2 (MLC2), which was inhibited by preincubation with the protein kinase C antagonist calphostin C [18].
  • PKA activation by beta-adrenoreceptor (isoproterenol) stimulation results in stoichiometric phosphorylation of troponin I (TnI) and C-protein [19].
  • Phosphorylation by cyclic AMP-dependent protein kinase (PKA) isolated from rat skeletal muscle reduced the sensitivity of TnI to degradation [20].
  • The genetically defined TnI mutants used were T144A, S43A/S45A, S43A/S45A/T144A (in which the PKC phosphorylation sites Thr-144 and Ser-43/Ser-45 were respectively substituted by Ala) and N32 (in which the first 32 amino acids in the NH2-terminal sequence containing Ser-23/Ser-24 were deleted) [16].
  • In addition, propofol stimulated dose-dependent phosphorylation of TnI and MLC2 [17].
 

Enzymatic interactions of Tnni3

  • These data demonstrate that TnI and C-protein are phosphorylated in myocardial cells by both PKA and PKC, resulting in different functional consequences in each case [19].
 

Regulatory relationships of Tnni3

 

Other interactions of Tnni3

 

Analytical, diagnostic and therapeutic context of Tnni3

  • In situ hybridization studies show that cardiac and slow skeletal TnI mRNAs are coexpressed in the rat heart from embryonic day 11 throughout fetal and perinatal stages [10].
  • Western-blot analysis with monoclonal antibodies against TnI and TnT showed that mu-calpain was at least ten times more active than m-calpain in degrading TnI and TnT both in vitro and in situ [20].
  • Immunoblotting analysis showed that development of the rat heart myofibrils is associated with isoform switching from slow skeletal TnI to cardiac TnI and from a slow mobility isoform of TnT (TnT1) to a faster Mr isoform (TnT2 [21].
  • We have isolated and characterized modified TnI products in isolated rat hearts after 0, 15, or 60 minutes of ischemia followed by 45 minutes of reperfusion using affinity chromatography with cardiac troponin C (TnC) and an anti-TnI antibody, immunological mapping, reversed-phase high-performance liquid chromatography, and mass spectrometry [3].
  • Titration of TnI replacement from >90% to <30% revealed a dominant functional effect of slow skeletal TnI to modulate regulation [22].

References

  1. Histidine button engineered into cardiac troponin I protects the ischemic and failing heart. Day, S.M., Westfall, M.V., Fomicheva, E.V., Hoyer, K., Yasuda, S., La Cross, N.C., D'Alecy, L.G., Ingwall, J.S., Metzger, J.M. Nat. Med. (2006) [Pubmed]
  2. Role of troponin I proteolysis in the pathogenesis of stunned myocardium. Gao, W.D., Atar, D., Liu, Y., Perez, N.G., Murphy, A.M., Marban, E. Circ. Res. (1997) [Pubmed]
  3. Troponin I degradation and covalent complex formation accompanies myocardial ischemia/reperfusion injury. McDonough, J.L., Arrell, D.K., Van Eyk, J.E. Circ. Res. (1999) [Pubmed]
  4. Altered phosphorylation and calcium sensitivity of cardiac myofibrillar proteins during sepsis. Wu, L.L., Tang, C., Liu, M.S. Am. J. Physiol. Regul. Integr. Comp. Physiol. (2001) [Pubmed]
  5. Molecular basis of depression of Ca2+ sensitivity of tension by acid pH in cardiac muscles of the mouse and the rat. Ding, X.L., Akella, A.B., Sonnenblick, E.H., Rao, V.G., Gulati, J. J. Card. Fail. (1996) [Pubmed]
  6. Thin filament protein dynamics in fully differentiated adult cardiac myocytes: toward a model of sarcomere maintenance. Michele, D.E., Albayya, F.P., Metzger, J.M. J. Cell Biol. (1999) [Pubmed]
  7. Preload induces troponin I degradation independently of myocardial ischemia. Feng, J., Schaus, B.J., Fallavollita, J.A., Lee, T.C., Canty, J.M. Circulation (2001) [Pubmed]
  8. Calpain-mediated proteolytic cleavage of troponin I induced by hypoxia or metabolic inhibition in cultured neonatal cardiomyocytes. Kositprapa, C., Zhang, B., Berger, S., Canty, J.M., Lee, T.C. Mol. Cell. Biochem. (2000) [Pubmed]
  9. Altered phosphorylation of sarcoplasmic reticulum contributes to the diminished contractile response to isoproterenol in hypertrophied rat hearts. Szymanska, G., Strömer, H., Silverman, M., Belu-John, Y., Morgan, J.P. Pflugers Arch. (1999) [Pubmed]
  10. Developmental expression of rat cardiac troponin I mRNA. Ausoni, S., De Nardi, C., Moretti, P., Gorza, L., Schiaffino, S. Development (1991) [Pubmed]
  11. Experimental diabetes is associated with functional activation of protein kinase C epsilon and phosphorylation of troponin I in the heart, which are prevented by angiotensin II receptor blockade. Malhotra, A., Reich, D., Reich, D., Nakouzi, A., Sanghi, V., Geenen, D.L., Buttrick, P.M. Circ. Res. (1997) [Pubmed]
  12. Protein kinase C phosphorylation of cardiac troponin I and troponin T inhibits Ca(2+)-stimulated MgATPase activity in reconstituted actomyosin and isolated myofibrils, and decreases actin-myosin interactions. Noland, T.A., Kuo, J.F. J. Mol. Cell. Cardiol. (1993) [Pubmed]
  13. Structure and regulation of the mouse cardiac troponin I gene. Ausoni, S., Campione, M., Picard, A., Moretti, P., Vitadello, M., De Nardi, C., Schiaffino, S. J. Biol. Chem. (1994) [Pubmed]
  14. Switching of troponin I: Ca(2+) and myosin-induced activation of heart muscle. Robinson, J.M., Dong, W.J., Xing, J., Cheung, H.C. J. Mol. Biol. (2004) [Pubmed]
  15. Role of troponin I phosphorylation in protein kinase C-mediated enhanced contractile performance of rat myocytes. Westfall, M.V., Borton, A.R. J. Biol. Chem. (2003) [Pubmed]
  16. 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. Noland, T.A., Raynor, R.L., Jideama, N.M., Guo, X., Kazanietz, M.G., Blumberg, P.M., Solaro, R.J., Kuo, J.F. Biochemistry (1996) [Pubmed]
  17. Propofol increases phosphorylation of troponin I and myosin light chain 2 via protein kinase C activation in cardiomyocytes. Kanaya, N., Gable, B., Murray, P.A., Damron, D.S. Anesthesiology (2003) [Pubmed]
  18. Arachidonic acid-dependent phosphorylation of troponin I and myosin light chain 2 in cardiac myocytes. Damron, D.S., Darvish, A., Murphy, L., Sweet, W., Moravec, C.S., Bond, M. Circ. Res. (1995) [Pubmed]
  19. Protein kinase C-mediated phosphorylation of troponin I and C-protein in isolated myocardial cells is associated with inhibition of myofibrillar actomyosin MgATPase. Venema, R.C., Kuo, J.F. J. Biol. Chem. (1993) [Pubmed]
  20. Specific degradation of troponin T and I by mu-calpain and its modulation by substrate phosphorylation. Di Lisa, F., De Tullio, R., Salamino, F., Barbato, R., Melloni, E., Siliprandi, N., Schiaffino, S., Pontremoli, S. Biochem. J. (1995) [Pubmed]
  21. Identification and functional significance of troponin I isoforms in neonatal rat heart myofibrils. Martin, A.F., Ball, K., Gao, L.Z., Kumar, P., Solaro, R.J. Circ. Res. (1991) [Pubmed]
  22. Sarcomere thin filament regulatory isoforms. Evidence of a dominant effect of slow skeletal troponin I on cardiac contraction. Metzger, J.M., Michele, D.E., Rust, E.M., Borton, A.R., Westfall, M.V. J. Biol. Chem. (2003) [Pubmed]
 
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