Phosphorylation-dependent interactions of myosin-binding protein C and troponin coordinate the myofilament response to protein kinase A

Sevrieva, Ivanka; Ponnam, Saraswathi; Irving, Malcolm; Kampourakis, Thomas; Sun, Yin-Biao

doi:10.1016/j.jbc.2022.102767

Cited by 6 publications

(15 citation statements)

References 99 publications

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“…Our group (Greenman et al., 2021 ; Ng et al., 2022 ) and others (Budde et al., 2021 ; Sevrieva et al., 2023 ; van der Velden et al., 2003 ) have shown that phosphorylation of myofilament proteins (including cTnI and myosin binding protein C) is associated with changes in Ca 2+ sensitivity. CO activates the soluble guanylate cyclase (sGC) pathway to phosphorylate cytosolic (e.g., L‐type Ca 2+ channel, ryanodine receptor) and myofilament proteins such as TnI at Ser23/24 (Layland et al., 2002 ; Stone & Marletta, 1994 ).…”

Section: Discussionmentioning

confidence: 86%

The carbon monoxide prodrug oCOm‐21 increases Ca²⁺ sensitivity of the cardiac myofilament

Payne,

Nie,

Diffee

et al. 2024

Physiological Reports

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Patients undergoing cardiopulmonary bypass procedures require inotropic support to improve hemodynamic function and cardiac output. Current inotropes such as dobutamine, can promote arrhythmias, prompting a demand for improved inotropes with little effect on intracellular Ca2+ flux. Low‐dose carbon monoxide (CO) induces inotropic effects in perfused hearts. Using the CO‐releasing pro‐drug, oCOm‐21, we investigated if this inotropic effect results from an increase in myofilament Ca2+ sensitivity. Male Sprague Dawley rat left ventricular cardiomyocytes were permeabilized, and myofilament force was measured as a function of ‐log [Ca2+] (pCa) in the range of 9.0–4.5 under five conditions: vehicle, oCOm‐21, the oCOm‐21 control BP‐21, and levosimendan, (9 cells/group). Ca2+ sensitivity was assessed by the Ca2+ concentration at which 50% of maximal force is produced (pCa50). oCOm‐21, but not BP‐21 significantly increased pCa50 compared to vehicle, respectively (pCa50 5.52 vs. 5.47 vs. 5.44; p < 0.05). No change in myofilament phosphorylation was seen after oCOm‐21 treatment. Pretreatment of cardiomyocytes with the heme scavenger hemopexin, abolished the Ca2+ sensitizing effect of oCOm‐21. These results support the hypothesis that oCOm‐21‐derived CO increases myofilament Ca2+ sensitivity through a heme‐dependent mechanism but not by phosphorylation. Further analyses will confirm if this Ca2+ sensitizing effect occurs in an intact heart.

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Section: Discussionmentioning

confidence: 86%

The carbon monoxide prodrug oCOm‐21 increases Ca²⁺ sensitivity of the cardiac myofilament

Payne,

Nie,

Diffee

et al. 2024

Physiological Reports

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“…With pseudo-phosphorylation at Ser 23 and Ser 24, they predict the unique N-terminal domain interacts, with both the N-lobe of cTnC interfering with Sw peptide binding and with Tm resulting in promotion of the off state of the thin filament. In stark contrast to these predictions, studies by Sevrieva et al [49] employing isolated myofibrils and skinned trabeculae preparations with authentically phosphorylated cTnI and cMyBP-C reported that cTnI phosphorylation alone increased Ca-sensitivity of trabeculae force generation at short and long sarcomere lengths. When both cTnI and cMyBP-C were phosphorylated, compared to controls there was an increase in force only at long sarcomere lengths.…”

Section: Regulation By Sarcomere Protein Phosphorylationmentioning

confidence: 86%

“…Among the many sites and types of PTMs in sarcomere proteins, phosphorylations of cTnI and cMyBP-C at their unique N-terminal domains have taken on prominent roles in tuning tension and dynamics to common physiological demands on the heart. Both mechanisms have been well-studied and discussed for some time but have been challenged by recent data [31,49]. In the case of cMyBP-C, we mentioned above that a predicted shift in SRX/DRX ratio with phosphorylation was not detected in the intact electrically stimulated trabeculae studied by nano-meter x-ray diffraction [31].…”

Section: Regulation By Sarcomere Protein Phosphorylationmentioning

confidence: 92%

“…It has also been proposed that there are direct interactions between cMyBP-C and cTnI that coordinate effects of phosphorylation of these proteins. [49]. However, it is not clear how these interactions may modulate inhibition.…”

Section: Cross-bridge On/off States and Control Of Tension/wall Stressmentioning

confidence: 99%

“…Apart from these findings in the x-ray analysis, the detailed mechanisms, and effects of cTnI phosphorylation at its N-terminus Ser residues have also been challenged in the literature [49]. For nearly 50 years, although there have been reports of differences in the altered molecular signaling with cTnI phosphorylation at S23, S24, there has been general agreement that the phosphorylation is a negative regulator of myofilament response to Ca 2+ and an important element in the lusitropic response to β-adrenergic stimulation [64,65].…”

Section: Regulation By Sarcomere Protein Phosphorylationmentioning

confidence: 99%

See 2 more Smart Citations

Emerging Concepts of Mechanisms Controlling Cardiac Tension: Focus on Familial Dilated Cardiomyopathy (DCM) and Sarcomere-Directed Therapies

Solaro,

Goldspink,

Wolska

2024

Preprint

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Novel therapies for treatment of familial dilated cardiomyopathy (DCM) are lacking. Triggers for the progression of the disorder commonly occur due to specific gene variants that affect the production of sarcomeric/cytoskeletal proteins. Generally these variants cause a decrease in tension by the myofilaments, resulting in signaling abnormalities within the micro-environment which over time result in structural and functional maladaptations leading to heart failure (HF). Current concepts support the hypothesis that the mutant sarcomere proteins induce a causal depression in the tension time integral (TTI) of linear preparations of cardiac muscle. However, molecular mechanisms underlying tension generation particularly in relation to mutant proteins and their impact on sarcomere molecular signaling, are currently the subject of controversy. Thus, there is a need for clarification as to how mutant proteins affect sarcomere molecular signaling in the etiology and progression of DCM. A main topic in this controversy is the control of the number of tension generating myosin heads reacting with the thin filament. One line of investigation proposes that this number is determined by changes in the ratio of myosin heads in a sequestered super-relaxed state (SRX) or in a disordered relaxed state (DRX) poised for force generation upon Ca-activation of the thin filament. Contrasting evidence from nanometer–micrometer-scale x-ray diffraction in intact trabeculae indicates that the SRX/DRX states may have a lesser role. Instead, the proposal is that myosin heads are in a basal OFF state in relaxation then transfer to an ON state through a mechano-sensing mechanism induced during early thin filament activation and increasing thick filament strain. Recent evidence about the modulation of these mechanisms by protein phosphorylation has also introduced a need for reconsidering control of tension. We discuss these mechanisms that lead to different ideas related to how tension is controlled and disturbed by mutant sarcomere proteins linked to DCM including cardiac myosin, myosin-binding protein C, titin filaments, and thin filaments. Resolving the various mechanisms and incorporating them into a unified concept is crucial for gaining a comprehensive understanding of DCM. This deeper understanding is not only important for diagnosis and treatment strategies with small molecules, but also for understanding the reciprocal signaling processes that occur between cardiac myocytes and their micro-environment. By unraveling these complexities, we can pave the way for improved therapeutic interventions for managing DCM.

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Cardiac ischemic preconditioning promotes cMyBP-C phosphorylation by inhibiting the calpain-mediated proteolysis

Liang,

Aisa,

Sun

et al. 2023

Experimental Cell Research

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Phosphorylation-dependent interactions of myosin-binding protein C and troponin coordinate the myofilament response to protein kinase A

Cited by 6 publications

References 99 publications

The carbon monoxide prodrug oCOm‐21 increases Ca²⁺ sensitivity of the cardiac myofilament

The carbon monoxide prodrug oCOm‐21 increases Ca²⁺ sensitivity of the cardiac myofilament

Emerging Concepts of Mechanisms Controlling Cardiac Tension: Focus on Familial Dilated Cardiomyopathy (DCM) and Sarcomere-Directed Therapies

Cardiac ischemic preconditioning promotes cMyBP-C phosphorylation by inhibiting the calpain-mediated proteolysis

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Phosphorylation-dependent interactions of myosin-binding protein C and troponin coordinate the myofilament response to protein kinase A

Cited by 6 publications

References 99 publications

The carbon monoxide prodrug oCOm‐21 increases Ca2+ sensitivity of the cardiac myofilament

The carbon monoxide prodrug oCOm‐21 increases Ca2+ sensitivity of the cardiac myofilament

Emerging Concepts of Mechanisms Controlling Cardiac Tension: Focus on Familial Dilated Cardiomyopathy (DCM) and Sarcomere-Directed Therapies

Cardiac ischemic preconditioning promotes cMyBP-C phosphorylation by inhibiting the calpain-mediated proteolysis

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Product

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The carbon monoxide prodrug oCOm‐21 increases Ca²⁺ sensitivity of the cardiac myofilament

The carbon monoxide prodrug oCOm‐21 increases Ca²⁺ sensitivity of the cardiac myofilament