Phosphorylation of the inhibitory subunit of troponin and its effect on the calcium dependence of cardiac myofibril adenosine triphosphatase

Ray, Keith P.; England, Paul

doi:10.1016/0014-5793(76)80716-8

Cited by 189 publications

(95 citation statements)

References 24 publications

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“…Elucidation 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 in the control of cardiac contractility [6,7]. Although it had been reported that phosphorylation of this region depressed sarcomeric response to Ca 2+ and increased cross-bridge kinetics [2,3], studies with transgenic models have provided the strongest evidence for a critical role of Tn, especially cTnI, in cardiac function.…”

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

105

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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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

105

119

View full text Add to dashboard Cite

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“…Cardiac TnI differs from its skeletal muscle counterpart by possessing an N-terminal extension (30-33 amino acid residues in length depending on the species) that may be phosphorylated at adjacent serine residues [12,13]. Phosphorylation of TnI by protein kinase A (PKA) decreases the Ca 2+ sensitivity of the myofilaments as indicated by the higher Ca 2+ concentration required to produce 50% activation of the regulated actomyosin [14] and myofibrillar ATPases [15,16] and of force development in skinned fibres [8]. In the heart, phosphorylation of TnI by PKA occurs following fladrenergic stimulation [17] and may be considered as an adaptive mechanism to prevent overstimulation.…”

Section: Introductionmentioning

confidence: 99%

Reconstitution of skinned cardiac fibres with human recombinant cardiac troponin‐I mutants and troponin‐C

et al. 1995

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“…This bisphosphorylation desensitizes the thin filaments to Ca 2ϩ by 0.2-0.4 pCa units (17)(18)(19) due to an increase in the rate of Ca 2ϩ dissociation from the N-terminal regulatory site on TnC (19). The faster release of Ca 2ϩ produces faster relaxation of skinned fibers upon rapid Ca 2ϩ chelation (20).…”

mentioning

confidence: 99%

Structural Consequences of Cardiac Troponin I Phosphorylation

Ward

Cornes

Trayer

2002

Journal of Biological Chemistry

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␤-Adrenergic stimulation of the heart results in bisphosphorylation of the N-terminal extension of cardiac troponin I (TnI). Bisphosphorylation of TnI reduces the affinity of the regulatory site on troponin C (TnC) for Ca 2؉ by increasing the rate of Ca 2؉ dissociation. What remains unclear is how the phosphorylation signal is transmitted from one subunit of troponin to another. We have produced a series of mutations in the N-terminal extension of TnI designed to further our understanding of the mechanisms involved. The ability of phosphorylation of the mutant TnIs to affect Ca 2؉ sensitivity has been assessed. We find that the Pro residues found in a conserved (Xaa-Pro) 4 motif N-terminal to the phosphorylation sites are not required for the effect of the Nterminal extension on Ca 2؉ binding in the presence or absence of phosphorylation. Our experiments also reveal that the full effects of phosphorylation are seen even when residues 1-15 of TnI are deleted. If further residues are removed, not only does the effect of phosphorylation diminish but deletion of the N-terminal extension mimics phosphorylation. We propose that TnI residues 16 -29 bind to TnC stabilizing the "open" Ca 2؉ -bound state. Phosphorylation (or deletion) prevents this binding, accelerating Ca 2؉ release.

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Phosphorylation of the inhibitory subunit of troponin and its effect on the calcium dependence of cardiac myofibril adenosine triphosphatase

Cited by 189 publications

References 24 publications

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

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

Reconstitution of skinned cardiac fibres with human recombinant cardiac troponin‐I mutants and troponin‐C

Structural Consequences of Cardiac Troponin I Phosphorylation

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