Changes in Cardiac Contractility Related to Calcium-Mediated Changes in Phosphorylation of Myosin-Binding Protein C

McClellan, George; Kulikovskaya, Irina; Winegrad, Saul

doi:10.1016/s0006-3495(01)75765-7

Cited by 93 publications

(112 citation statements)

References 31 publications

(58 reference statements)

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“…cMyBP-C is dephosphorylated during low-flow ischemia (17) and in I-R-based heart failure models (14). Decreased phosphorylation would have the net effect of increasing thick filament packing density, possibly leading to reduced calcium-activated force generation (25).…”

Section: Discussionmentioning

confidence: 99%

Cardiac myosin binding protein c phosphorylation is cardioprotective

Sadayappan

Osińska

Klevitsky

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

190

294

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Cardiac myosin binding protein C (cMyBP-C) has three phosphorylatable serines at its N terminus (Ser-273, Ser-282, and Ser-302), and the residues' phosphorylation states may alter thick filament structure and function. To examine the effects of cMyBP-C phosphorylation, we generated transgenic mice with cardiac-specific expression of a cMyBP-C in which the three phosphorylation sites were mutated to aspartic acid, mimicking constitutive phosphorylation (cMyBP-C AllP؉ ). The allele was bred into a cMyBP-C null background (cMyBP-C (t/t) ) to ensure the absence of endogenous dephosphorylated cMyBP-C. cMyBP-C AllP؉ was incorporated normally into the cardiac sarcomere and restored normal cardiac function in the null background. However, subtle changes in sarcomere ultrastructure, characterized by increased distances between the thick filaments, indicated that phosphomimetic cMyBP-C affects thick-thin filament relationships, and yeast two-hybrid data and pull-down studies both showed that charged residues in these positions effectively prevented interaction with the myosin heavy chain. Confirming the physiological relevance of these data, the cMyBP-C AllP؉:(t/t) hearts were resistant to ischemia-reperfusion injury. These data demonstrate that cMyBP-C phosphorylation functions in maintaining thick filament spacing and structure and can help protect the myocardium from ischemic injury.heart ͉ ischemia C ardiac myosin binding protein C (cMyBP-C) is localized to the sarcomere's thick filaments where it has structural and regulatory functions. MYBPC3 mutations account for 20-30% of all mutations linked to familial hypertrophic cardiomyopathy (1). cMyBP-C belongs to the intracellular Ig superfamily and is composed of Ig and fibronectin type-3 repeating domains (Fig. 1A). It is present not only in cardiac muscle, but also in skeletal muscle before the skeletal muscle-type isoforms are expressed, suggesting that the cardiac isoform is functional in early myofibrillogenesis and regenerating muscle (2, 3). cMyBP-C may modulate myosin assembly (4) and stabilize thick filaments (5). It binds titin via domains C8-C10 (6) and actin in the Pro-Alarich sequences between the C0 and C1 domains (7), which appear to be important for the precise arrangement of the actin-myosin filaments. Compared with the two skeletal muscle isoforms, the cardiac isoform contains an extra Ig domain at the N terminus (C0), an insertion of 28 residues within the C5 domain, and three potential phosphorylation sites that are substrates for cAMP-dependent PKA, Ca 2ϩ -calmodulin-activated kinase, and PKC (8). This region is located between the C1 and C2 domains of the N terminus, which binds to the subfragment 2 (S2) segment of myosin close to the lever arm domain (9-11), and this interaction may be dynamically regulated by the differential phosphorylation of cMyBP-C (12). cMyBP-C is the only thick filament protein that is differentially phosphorylated at multiple sites by the enzymes PKA, PKC, and Ca 2ϩ -calmodulin-activated kinase (13). Reconstitution studie...

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Section: Discussionmentioning

confidence: 99%

Cardiac myosin binding protein c phosphorylation is cardioprotective

Sadayappan

Osińska

Klevitsky

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

190

294

View full text Add to dashboard Cite

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“…Cardiac myosin-binding protein C (cMyBP-C) is a thick filament protein containing accessible phosphorylation sites (141). However, the exact physiological function of cMyBP-C is not fully understood, and it is not clear whether the protein plays a role in the regulation of contraction through phosphorylation (131,(142)(143)(144). It should be mentioned that Garvey et al (145) have provided evidence against the selective cMyBP-C phosphorylation having any role in modulating contractility.…”

Section: Myofibrillar Assembly In Congestive Hfmentioning

confidence: 99%

“…However, recent data suggest that cMyBP-C phosphorylation alters the structure of the thick filament and may modify the kinetics of cross-bridge cycling (146). Furthermore, it may modulate myosin ATPase activity (143,144), but its in vivo phosphorylation still needs to be clearly demonstrated.…”

Section: Myofibrillar Assembly In Congestive Hfmentioning

confidence: 99%

Myofibrillar remodelling in cardiac hypertrophy, heart failure and cardiomyopathies

Macháčková¹,

Barta²,

Dhalla³

2006

Canadian Journal of Cardiology

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“…All three phosphorylation sites can be phosphorylated by Ca 2+ / calmodulin-dependent (CaM-II) kinases, including the endogenous CaM-II-like kinase that co-purifies with MyBPC [43,44]. The first phosphate must be added by a CaM-II kinase to residue S284, to make the other phosphorylation sites accessible [45,46]. Upon adrenergic stimulation, cAMP-dependent protein kinase can phosphorylate the other two sites (S275 and S304).…”

Section: Figmentioning

confidence: 99%