Published online before print June 6, 2002, doi: 10.1161/01.RES.0000024389.03152.22
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Submitted on January 18, 2002
Revised on May 22, 2002
Accepted on May 22, 2002
Actin Capping Protein. An Essential Element in Protein Kinase Signaling to the Myofilaments
W. Glen Pyle ;
From the Department of Physiology and Biophysics (W.G.P., M.P.S., P.P.d.T., R.J.S.), University of Illinois at Chicago, Chicago, Ill; the Biological Sciences Department (M.C.H.), Minnesota State University, Mankato, Minn; and the Department of Cell Biology and Physiology (J.A.C.), Washington University School of Medicine, St Louis, Mo.
* To whom correspondence should be addressed. E-mail: solarorj{at}uic.edu.
Actin capping protein (CapZ) binds the barbed ends of actin at sarcomeric Z-lines. In addition to anchoring actin, Z-discs bind protein kinase C (PKC). Although CapZ is crucial for myofibrillogenesis, its role in muscle function and intracellular signaling is unknown. We hypothesized that CapZ downregulation would impair myocardial function and disrupt PKC-myofilament signaling by impairing PKC--Z-disc interaction. To test these hypotheses, we examined transgenic (TG) mice in which cardiac CapZ protein is reduced. Fiber bundles were dissected from papillary muscles and detergent extracted. Some fiber bundles were treated with PKC activators phenylephrine (PHE) or endothelin (ET) before detergent extraction. We simultaneously measured Ca2+-dependent tension and actomyosin MgATPase activity. CapZ downregulation increased myofilament Ca2+ sensitivity without affecting maximum tension or actomyosin MgATPase activity. Maximum tension and actomyosin MgATPase activity were decreased after PHE or ET treatment of wild-type (WT) muscle. Fiber bundles from TG hearts did not respond to PHE or ET. Immunoblot analysis revealed an increase in myofilament-associated PKC-
after PHE or ET exposure of WT preparations. In contrast, myofilament-associated PKC- was decreased after PHE or ET treatment in TG myocardium. Protein levels of myofilament-associated PKC-ß were decreased in TG ventricle. C-protein and troponin I phosphorylation was increased after PHE or ET treatment in WT and TG hearts. Basal phosphorylation levels of C-protein and troponin I were higher in TG myocardium. These results indicate that downregulation of CapZ, or other changes associated with CapZ downregulation, increases cardiac myofilament Ca2+ sensitivity, inhibits PKC-mediated control of myofilament activation, and decreases myofilament-associated PKC-ß.
Key words: actin capping protein • protein kinase C • myofilaments • Z-discs
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