Gene transfer of troponin I isoforms, mutants, and chimeras.
Thin filament proteins play an essential role in the regulation of myocardial pressure development. Within the thin filament of the sarcomere, troponin I (TnI) plays a key role in regulating the Ca(2+) sensitivity of force. During myocardial development, there is a transition in TnI isoform expression from the slow skeletal isoform (ssTnI) in embryonic/fetal myocardium to the cardiac isoform (cTnI) expressed in adult hearts. Over a similar developmental time window, the calcium sensitivity of force development also decreases. Gene transfer of ssTnI, and chimeras derived from ssTnI and cTnI, into adult ventricular myocytes have provided insights into the isoform-specific domains of TnI responsible for differentially influencing myofilament Ca(2+) sensitivity. Two separate isoform-specific regions, located in the carboxyl- and amino-portions of the protein, have been identified by comparing Ca(2+)-activated isometric tension in myocytes expressing the TnI isoforms or chimeras. The carboxyl-portion of TnI also contributes to isoform-dependent differences in myofilament sensitivity to acidic pH, which ensues during several myocardial disease states. In contrast, the diminished Ca(2+) sensitivity observed in response to beta-adrenergic-mediated phosphorylation of cardiac TnI requires the amino-portion of the cardiac TnI isoform yet, does not depend on the presence of a specific isoform in the carboxyl-region of TnI. Recent studies with a mutation linked to hypertrophic cardiomyopathy have demonstrated that changes in protein charge also influence the ability of TnI isoforms to regulate myofilament Ca(2+) sensitivity. Information gained from these, and future studies on more localized and specific changes in the amino acid sequence, may one day lead to the use of genetically engineered TnI for therapeutic manipulation of contractile function.
Westfall
Margaret V
MV
Department of Physiology, University of Michigan, 1301 E. Catherine St., Ann Arbor, MI 48109, USA. metzgerj@umich.edu
Metzger
Joseph M
JM
D008841:Actin Cytoskeleton / Q000378:metabolism; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002118:Calcium / Q000737:chemistry / Q000378:metabolism; D018014:Gene Transfer Techniques; D006321:Heart / Q000196:embryology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D032342:Muscle Cells / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D009154:Mutation; D009206:Myocardium / Q000166:cytology / Q000473:pathology; D010766:Phosphorylation; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D014336:Troponin / Q000737:chemistry* / Q000235:genetics*; D019210:Troponin I / Q000737:chemistry / Q000378:metabolism
D020033:Protein Isoforms; D014336:Troponin; D019210:Troponin I; D002118:Calcium