The Miscommunicative Cardiac Cell: When Good Proteins Go Bad

Abstract

Troponin (Tn) is made up of three subunits, troponin T (TnT), troponin I (TnI), and troponin C (TnC). In cardiac muscle, TnI can exist as two isoforms, slow skeletal TnI (ssTnI) or cardiac TnI (cTnI), whereas TnT occurs as multiple isoforms. The predominant form of TnI in fetal cardiac muscle is ssTnI, which is derived from a different gene than cTnI. However, the predominant form of cardiac TnT (cTnT) in fetal muscle is cTnT1, which is derived from the same gene that produces the adult cTnT isoform (cTnT3). Fetal cardiac muscle is more sensitive to Ca(2+) than adult muscle and this may be due in part to the fetal cTnT1 and ssTnI isoforms. cTnT1 and/or ssTnI by themselves cause a significant increase in Ca(2+) sensitivity when compared to cTnT3 and/or cTnI. Mutations in the gene for cTnT can cause hypertrophic cardiomyopathy or dilated cardiomyopathy (DCM). Investigation of DCM mutations in the fetal cTnT1 isoform showed that the cTnT isoform is an important determinant of the effect of the mutation. The TnI isoform also affects the physiological function of the cardiac muscle. The presence of both the fetal TnT isoform, containing a DCM mutation, and ssTnI results in larger changes in Ca(2+) sensitivity than the same DCM mutant in the adult TnT isoform and in the presence of cTnI (when compared to their respective wild-type TnT controls). These recent results suggest that some mutations may have different severities in fetal and adult hearts.

Cardiac Sarcomere Signaling in Health and Disease

“…The portion of TnI that is involved in this mechanism is referred to as the switch region and this binding between TnI and TnC helps to remove the inhibitory arm of TnI from the actin-Tm interface exposing myosin binding sites found on actin [2,17,19]. This interaction is crucial to the development of force in cardiac muscle and even single amino acid changes can lead to impaired function [23,[25][26][27]. Additionally, the mechanism is highly tunable through post-translational modifications such as phosphorylation changes, which will be discussed below.…”

Molecular mechanisms of cardiomyopathy phenotypes associated with myosin light chain mutations

“…The clinical symptom of DCM is heart failure (HF), which is often associated with arrhythmia and SCD (Hershberger et al 2013). Distinct from HCM, which in most cases is a genetic disease, DCM can be caused by a variety of factors, including ischemia, alcohol toxicity and viral infections (Gomes et al 2005; Szczesna-Cordary et al 2012). It is estimated that only 25–48 % of all DCM cases are due to familial and genetic factors (Kamisago et al 2000; Millat et al 2011).…”