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Received April 17, 2002
Accepted after revision May 15, 2002
1 Veterans Affairs Medical Center, Cardiology Division, 111C, 4150 Clement Street, San Francisco, CA 94121, USA
2 Centre for Immunology, St. Vincent's Hospital, Sydney, NSW, 2010, Australia
3 Biomedical Systems Research Group, Division of Information and Communication Sciences, Macquarie University, NSW, 2109, Australia.
* To whom correspondence should be addressed. E-mail: lynnet3{at}itsa.ucsf.edu.
Inotropic agents that increase the intracellular levels of cAMP have been shown to increase crossbridge turnover kinetics in intact rat ventricular muscle, as measured by the parameter fmin (the frequency at which dynamic stiffness is minimum). These agents are also known to increase the level of phosphorylation of two candidate myofibrillar proteins: myosin binding protein C (MyBPC) and Troponin I (TnI), but have no effect on myosin light chain 2 phosphorylation (MyLC2). The aim of this study was to investigate whether the phosphorylation of TnI and/or MyBPC was responsible for the increase in crossbridge cycling kinetics (as captured by fmin) seen with the elevation of cAMP within cardiac tissue. Using barium-activated intact rat papillary muscle, we investigated the actions of isobutylmethylxanthine (IBMX), an inhibitor of cAMP- dependent phosphatase, which simulates the action of ß-adrenergic agents, and the chemical phosphatase 2,3-butanedione monoxime (BDM), which has been shown to dephosphorylate a number of contractile proteins. The presence of 0.6 mM IBMX approximately doubled the fmin value of intact rat papillary muscle. This action was unaffected by the addition of BDM. In the presence of IBMX and BDM, the level of phosphorylation of MyBPC was unchanged, that of MyLC2 was reduced to 60 % of control, yet that of TnI was markedly increased (to 30 % above control levels). We conclude that TnI phosphorylation, mediated by cAMP-dependent protein kinase A, is the molecular basis for the enhanced crossbridge cycling seen during ß-adrenergic stimulation of the heart.
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