Gene transfer of troponin I isoforms, mutants, and chimeras

Margaret V. Westfall, Joseph M. Metzger

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

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 Ca2+ 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 Ca2+ sensitivity. Two separate isoform-specific regions, located in the carboxyl- and amino- portions of the protein, have been identified by comparing Ca2+-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 Ca2+ sensitivity observed in response to β-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 Ca2+ 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.

Original languageEnglish (US)
Pages (from-to)169-174
Number of pages6
JournalAdvances in experimental medicine and biology
Volume538
StatePublished - Apr 19 2004

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