Faculty Collaboration Database

alpha-Adrenergic response and myofilament activity in mouse hearts lacking PKC phosphorylation sites on cardiac TnI. Am J Physiol Heart Circ Physiol 2002 Jun;282(6):H2397-405

Date

05/11/2002

Pubmed ID

12003851

DOI

10.1152/ajpheart.00714.2001

Scopus ID

2-s2.0-0036083710 (requires institutional sign-in at Scopus site)   59 Citations

Abstract

Protein kinase C (PKC)-mediated phosphorylation of cardiac myofilament (MF) proteins has been shown to depress the actomyosin interaction and may be important during heart failure. Biochemical studies indicate that phosphorylation of Ser(43) and Ser(45) of cardiac troponin I (cTnI) plays a substantial role in the PKC-mediated depression. We studied intact and detergent-extracted papillary muscles from nontransgenic (NTG) and transgenic (TG) mouse hearts that express a mutant cTnI (Ser43Ala, Ser45Ala) that lacks specific PKC-dependent phosphorylation sites. Treatment of NTG papillary muscles with phenylephrine (PE) resulted in a transient increase and a subsequent 62% reduction in peak twitch force. TG muscles showed no transient increase and only a 45% reduction in force. There was a similar difference in maximum tension between NTG and TG fiber bundles that had been treated with a phorbol ester and had received subsequent detergent extraction. Although levels of cTnI phosphorylation correlated with these differences, the TG fibers also demonstrated a decrease in phosphorylation of cardiac troponin T. The PKC-specific inhibitor chelerythrine inhibited these responses. Our data provide evidence that specific PKC-mediated phosphorylation of Ser(43) and Ser(45) of cTnI plays an important role in regulating force development in the intact myocardium.

Author List

Montgomery DE, Wolska BM, Pyle WG, Roman BB, Dowell JC, Buttrick PM, Koretsky AP, Del Nido P, Solaro RJ

Author

Jasmine C. Dowell MD Assistant Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Actin Cytoskeleton
Alkaloids
Animals
Benzophenanthridines
Binding Sites
Detergents
Enzyme Activation
Enzyme Inhibitors
Gene Expression
Heart
Mice
Mice, Transgenic
Mutation
Myocardial Contraction
Papillary Muscles
Phenanthridines
Phenylephrine
Phosphorylation
Phosphoserine
Protein Kinase C
Receptors, Adrenergic, alpha
Tetradecanoylphorbol Acetate
Troponin I