Identification of troponin C residues that increase mammalian cardiac myocyte contractility

Cardiac troponin C (cTnC) is a highly conserved Ca2+ binding protein that plays an essential role in cardiomyocyte contraction. Sequence differences between cTnC homologs have been shown to be responsible for differential Ca2+ sensitivity. A series of substitutions (D2N, V28I, L29Q and G30D) in salmonid cTnC (ScTnC) accounts for a two-fold higher Ca2+ affinity and sensitivity compared to mammalian cTnC (McTnC). The single L29Q substitution that is associated with familial hypertrophic cardiomyopathy (FHC) shows an approximately 35% increase in Ca2+ affinity and sensitivity. A skeletal-cardiac TnC chimeric construct confirms the N-terminal domain role as the main determinant of Ca2+ affinity and sensitivity. Increasing contractility through modification of Ca2+ sensitivity presents a novel means of treating a failing heart and thus the overall objective of this thesis is to provide further insights into cTnC structure and function which can be used in rational drug design for the treatment of heart failure.