Phosphorylation of troponin I and the inotropic effect of adrenaline in the perfused rabbit heart

Solaro, R. John; Moir, Arthur J. G.; Perry, S. V.

doi:10.1038/262615a0

Cited by 386 publications

(251 citation statements)

References 13 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

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“…15 Under the influence of b-adrenergic stimulation, cTnI becomes phosphorylated at Ser22 and Ser23 (also known as Ser23 and Ser24 including initial methionine) by cyclic AMPactivated protein kinase (PKA). 14,16 Phosphorylation of these ''PKA sites'' in cTnI regulates the Ca 2þ sensitivity of force development and MgATPase activity and may modulate the rate of cross-bridge cycling. 15 cTnI and other myofilament proteins are also targeted by additional protein kinases involved in signaling such as protein kinase C (PKC), [17][18][19][20][21][22] protein kinase D (PKD), 23,24 and p21-activated kinase (PAK).…”

Section: Introductionmentioning

confidence: 99%

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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“…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. The phosphorylation of cardiac TnI has been shown to reduce the affinity of TnC for Ca 2+ [18], thus, promoting more rapid relaxation [9].…”

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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Phosphorylation of troponin I and the inotropic effect of adrenaline in the perfused rabbit heart

Cited by 386 publications

References 13 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

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

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

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