Differential Roles of Cardiac Myosin-Binding Protein C and Cardiac Troponin I in the Myofibrillar Force Responses to Protein Kinase A Phosphorylation

Stelzer, Julian E.; Patel, Jitandrakumar R.; Walker, Jeffery W.; Moss, Richard L.

doi:10.1161/circresaha.107.153650

Cited by 152 publications

(222 citation statements)

References 49 publications

(75 reference statements)

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“…Myofilament structure, arrangement, and function are thought to remain intact in skinned myocytes, as observed in studies in which these preparations were used to assess force development and relaxation. 18,21,44 Therefore, phosphorylation of cTnI under the conditions used here indicates that AMPK is capable of phosphorylating cTnI when assembled in the Tn complex and associated with other myofilament contractile proteins. Moreover, cTnI Ser149 was a target site under these conditions.…”

Section: Phosphorylation Of Ctni In Skinned Rodent Myocytesmentioning

confidence: 72%

A preferred AMPK phosphorylation site adjacent to the inhibitory loop of cardiac and skeletal troponin I

Solis

Walker

2011

Protein Science

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5 0 -AMP-activated protein kinase (AMPK) is a serine/threonine protein kinase that is activated when cellular AMP to ATP ratios rise, potentially serving as a key regulator of cellular energetics. Among the known targets of AMPK are catabolic and anabolic enzymes, but little is known about the ability of this kinase to phosphorylate myofilament proteins and thereby regulating the contractile apparatus of striated muscles. Here, we demonstrate that troponin I isoforms of cardiac (cTnI) and fast skeletal (fsTnI) muscles are readily phosphorylated by AMPK. For cTnI, two highly conserved serine residues were identified as AMPK sites using a combination of high-resolution top-down electron capture dissociation mass spectrometry, 32 P-incorporation, synthetic peptides, phospho-specific antibodies, and site-directed mutagenesis. These AMPK sites in cTnI were Ser149 adjacent to the inhibitory loop and Ser22 in the cardiac-specific N-terminal extension, at the level of cTnI peptides, the intact cTnI subunit, whole cardiac troponin complexes and skinned cardiomyocytes. Phosphorylation time-course experiments revealed that Ser149 was the preferred site, because it was phosphorylated 12-16-fold faster than Ser22 in cTnI. Ser117 in fsTnI, analogous to Ser149 in cTnI, was phosphorylated with similar kinetics as cTnI Ser149. Hence, the master energy-sensing protein AMPK emerges as a possibly important regulator of cardiac and skeletal contractility via phosphorylation of a preferred site adjacent to the inhibitory loop of the thin filament protein TnI.

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Section: Phosphorylation Of Ctni In Skinned Rodent Myocytesmentioning

confidence: 72%

A preferred AMPK phosphorylation site adjacent to the inhibitory loop of cardiac and skeletal troponin I

Solis

Walker

2011

Protein Science

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“…Along these lines, Varian and Janssen [14] reported a frequency dependent decrease in myofilament sensitivity to Ca 2+ associated with increasing heart rates and most likely attributable to cTnI phosphorylation. The role of cTnI phosphorylation in the relaxant effect of adrenergic stimulation has also been emphasized in work reported by Stelzer et al [15] in studies of mice expressing cTnI-S23D/S24D against a cTnI and myosin binding protein C null background. These studies together with others provide compelling evidence for a prominent role of cTnI phosphorylation in the maintenance of power and frequency response in ejecting ventricles [13,[16][17][18][19].…”

Section: Specific Modifications In Troponin I Affect the Dynamics Andmentioning

confidence: 89%

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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“…MyBP-C is a substrate for PKA, PKC, and CamK II [7,14,15]. Phosphorylation of MyBP-C appears to be significantly involved in enhanced cross-bridge kinetics and therefore likely to be a significant functional mechanism along with TnI phosphorylation [16]. Phosphorylation of titin by PKA reduces passive tension [8].…”

Section: Changes To Myofilament Proteins and Molecular Mechanisms Of mentioning

confidence: 99%

“…For example, Wang and colleagues [90] used light and heavy acetic anhydride to differentially label TnI digests without and with PKC-b II treatment, and found that Thr144 could be phosphorylated by PKC-b II. Similarly, we used differential O 16 /O 18 labeling to quantify developmental phosphorylation changes and found three altered phosphorylation sites from LC2 and MyBP-C [104].…”

Section: Phosphorylationmentioning

confidence: 99%

“…For example, both MyBP-C and TnI can be phosphorylated by PKA during b-adrenergic stimulation [123]. To tease out their individual contribution to the increase cardiac contractility, mouse lines expressing non-PKA-phosphorylatable TnI and MyBP-C were examined [16]. Similar to concomitant phosphorylation, protein degradation can also occur simultaneously.…”

Section: Interactions Between and Within Different Types Of Protein Mmentioning

confidence: 99%

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Myofilament proteins: From cardiac disorders to proteomic changes

Yuan

Solaro

2008

Proteomics Clinical Apps

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Myofilament proteins of the cardiac sarcomere house the molecular machinery responsible for generating tension and pressure. Release of intracellular Ca 21 triggers myofilament tension generation and shortening, but the response to Ca 21 is modulated by changes in key regulatory proteins. We review how these proteomic changes are essential to adaptive physiological regulation of cardiac output and become maladaptive in cardiac disorders. We also review the essentials of proteomic techniques used to study myofilament protein changes, including degradation, isoform expression, phosphorylation and oxidation. Selected proteomic studies illustrate the applications of these approaches.

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Differential Roles of Cardiac Myosin-Binding Protein C and Cardiac Troponin I in the Myofibrillar Force Responses to Protein Kinase A Phosphorylation

Cited by 152 publications

References 49 publications

A preferred AMPK phosphorylation site adjacent to the inhibitory loop of cardiac and skeletal troponin I

A preferred AMPK phosphorylation site adjacent to the inhibitory loop of cardiac and skeletal troponin I

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

Myofilament proteins: From cardiac disorders to proteomic changes

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