scholarly journals Acceleration of Crossbridge Kinetics by Protein Kinase A Phosphorylation of Cardiac Myosin Binding Protein C Modulates Cardiac Function

2008 ◽  
Vol 103 (9) ◽  
pp. 974-982 ◽  
Author(s):  
Carl W. Tong ◽  
Julian E. Stelzer ◽  
Marion L. Greaser ◽  
Patricia A. Powers ◽  
Richard L. Moss
Keyword(s):  
Protein Kinase ◽  
Cardiac Function ◽  
Protein Kinase A ◽  
Protein C ◽  
Cardiac Myosin ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Crossbridge Kinetics ◽  
Myosin Binding ◽  
Kinase A

scholarly journals Protein kinase A–induced myofilament desensitization to Ca2+ as a result of phosphorylation of cardiac myosin–binding protein C

2010 ◽  
Vol 136 (6) ◽  
pp. 615-627 ◽  
Author(s):  
Peter P. Chen ◽  
Jitandrakumar R. Patel ◽  
Inna N. Rybakova ◽  
Jeffery W. Walker ◽  
Richard L. Moss
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Protein C ◽  
Binding Protein ◽  
Cardiac Myosin ◽  
Cross Bridge ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding ◽  
Kinase A

In skinned myocardium, cyclic AMP–dependent protein kinase A (PKA)-catalyzed phosphorylation of cardiac myosin–binding protein C (cMyBP-C) and cardiac troponin I (cTnI) is associated with a reduction in the Ca2+ responsiveness of myofilaments and an acceleration in the kinetics of cross-bridge cycling, although the respective contribution of these two proteins remains controversial. To further examine the relative roles that cTnI and cMyBP-C phosphorylation play in altering myocardial function, we determined the Ca2+ sensitivity of force (pCa50) and the activation dependence of the rate of force redevelopment (ktr) in control and PKA-treated mouse myocardium (isolated in the presence of 2,3-butanedione monoxime) expressing: (a) phosphorylatable cTnI and cMyBP-C (wild type [WT]), (b) phosphorylatable cTnI on a cMyBP-C–null background (cMyBP-C−/−), (c) nonphosphorylatable cTnI with serines23/24/43/45 and threonine144 mutated to alanines (cTnIAla5), and (d) nonphosphorylatable cTnI on a cMyBP-C–null background (cTnIAla5/cMyBP-C−/−). Here, PKA treatment decreased pCa50 in WT, cTnIAla5, and cMyBP-C−/− myocardium by 0.13, 0.08, and 0.09 pCa units, respectively, but had no effect in cTnIAla5/cMyBP-C−/− myocardium. In WT and cTnIAla5 myocardium, PKA treatment also increased ktr at submaximal levels of activation; however, PKA treatment did not have an effect on ktr in cMyBP-C−/− or cTnIAla5/cMyBP-C−/− myocardium. In addition, reconstitution of cTnIAla5/cMyBP-C−/− myocardium with recombinant cMyBP-C restored the effects of PKA treatment on pCa50 and ktr reported in cTnIAla5 myocardium. Collectively, these results indicate that the attenuation in myofilament force response to PKA occurs as a result of both cTnI and cMyBP-C phosphorylation, and that the reduction in pCa50 mediated by cMyBP-C phosphorylation most likely arises from an accelerated cross-bridge cycling kinetics partly as a result of an increased rate constant of cross-bridge detachment.

Protein kinase A–induced myofilament desensitization to Ca2+as a result of phosphorylation of cardiac myosin–binding protein C

2010 ◽  
Vol 191 (6) ◽  
pp. i17-i17
Author(s):  
Peter P. Chen ◽  
Jitandrakumar R. Patel ◽  
Inna N. Rybakova ◽  
Jeffery W. Walker ◽  
Richard L. Moss
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Protein C ◽  
Binding Protein ◽  
Cardiac Myosin ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding ◽  
Kinase A

scholarly journals Interaction between cardiac myosin-binding protein C and formin Fhod3

2018 ◽  
Vol 115 (19) ◽  
pp. E4386-E4395 ◽  
Author(s):  
Sho Matsuyama ◽  
Yohko Kage ◽  
Noriko Fujimoto ◽  
Tomoki Ushijima ◽  
Toshihiro Tsuruda ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Cardiac Function ◽  
Protein C ◽  
Binding Protein ◽  
Direct Interaction ◽  
Familial Hypertrophic Cardiomyopathy ◽  
Cardiac Myosin ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding

Mutations in cardiac myosin-binding protein C (cMyBP-C) are a major cause of familial hypertrophic cardiomyopathy. Although cMyBP-C has been considered to regulate the cardiac function via cross-bridge arrangement at the C-zone of the myosin-containing A-band, the mechanism by which cMyBP-C functions remains unclear. We identified formin Fhod3, an actin organizer essential for the formation and maintenance of cardiac sarcomeres, as a cMyBP-C–binding protein. The cardiac-specific N-terminal Ig-like domain of cMyBP-C directly interacts with the cardiac-specific N-terminal region of Fhod3. The interaction seems to direct the localization of Fhod3 to the C-zone, since a noncardiac Fhod3 variant lacking the cMyBP-C–binding region failed to localize to the C-zone. Conversely, the cardiac variant of Fhod3 failed to localize to the C-zone in the cMyBP-C–null mice, which display a phenotype of hypertrophic cardiomyopathy. The cardiomyopathic phenotype of cMyBP-C–null mice was further exacerbated by Fhod3 overexpression with a defect of sarcomere integrity, whereas that was partially ameliorated by a reduction in the Fhod3 protein levels, suggesting that Fhod3 has a deleterious effect on cardiac function under cMyBP-C–null conditions where Fhod3 is aberrantly mislocalized. Together, these findings suggest the possibility that Fhod3 contributes to the pathogenesis of cMyBP-C–related cardiomyopathy and that Fhod3 is critically involved in cMyBP-C–mediated regulation of cardiac function via direct interaction.

Abstract 231: Cardiac Myosin Binding Protein C Couples Cross-Bridge Cycling to Calcium Transients to Provide Normal Cardiac Function

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Yang Liu ◽  
Mahamed Abdalla ◽  
Himakarnika Alluri ◽  
Daniel Jupiter ◽  
Shannon Glaser ◽  
...  
Keyword(s):  
Body Weight ◽  
Cardiac Function ◽  
Protein C ◽  
Calcium Transients ◽  
Cardiac Myosin ◽  
Cross Bridge ◽  
Myosin Binding Protein ◽  
Myosin Binding Protein C ◽  
Myosin Binding ◽  
Normal Cardiac Function

A 40-year old American has a 20% chance of developing heart failure (HF) in his/her lifetime. Although cross-bridge cycling forms the basis for contraction and relaxation of the heart, mechanisms that modulate cross-bridge cycling are not completely understood, nor are the alterations in these processes in HF. Cardiac myosin binding protein-C (MyBPC3) is a component of heart muscle that is believed to regulate cross-bridge cycling kinetics. We hypothesize that MyBPC3 tunes cross-bridge cycling to the [Ca2+]i transient to produce normal cardiac function, which we tested using our MyBPC3 knockout (KO) mouse. Echocardiography showed that MyBPC3(KO) hearts exhibited abbreviated aortic ejection durations (AED) and AED/(period between heart beats) ratio compared to WT. MyBPC3(KO) hearts also had smaller velocity-time integrals which indicate smaller stroke volumes as a result of abbreviated ejection. Brain natriuretic peptide expression level, heart weight/body weight, and lung weight/body weight were all increased in MyBPC3(KO) mice, consistent with HF. MyBPC3(KO) mice also exhibit increased 1-year mortality. We used simultaneous twitch force and intracellular calcium [Ca2+]i measurements on intact papillary muscles to evaluate the consequences of losing cross-bridge cycling regulation on force response to changing [Ca2+]i transients. MyBPC3 (KO) myocardium exhibited abbreviated contractions despite slower calcium transients and an inability to accelerate relaxation with respect to peak contraction. Therefore, loss of MyBPC3-mediated coupling of cross-bridge cycling to the [Ca2+]i transient was associated with contractile dysfunction and HF.

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