Determining the calcium sensitivity of the hypertrophic cardiomyopathy-linked alpha-cardiac actin variant A331P

Despond, Evan A.
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University of Guelph

Hypertrophic cardiomyopathy (HCM) is a common inherited cardiovascular disease linked to sarcomere proteins. Over many years of research, a common hypothesis for this disease has emerged: protein variants cause an increase in calcium (Ca2+) sensitivity that leads to greater contractility, resulting in hypertrophy characteristic of HCM. Only one protein has shown to contradict this hypothesis, the α-cardiac actin (ACTC) variant A331P. In this thesis, A331P-ACTC was compared to wild-type recombinant- (WTrec-) ACTC and found to have a decrease in Ca2+ sensitivity, but with residual activity at low Ca2+ concentration, based on the actin-activated myosin ATPase and in vitro motility assays. My results indicate that Ca2+ sensitivity should not be the sole focus of research, which is supported by recent publications that raise additional considerations regarding HCM progression besides an increase in Ca2+ sensitivity. Finally, my research suggests that residual constitutive contraction is an additional mechanism for HCM development.

Actin, Hypertrophic cardiomyopathy, Calcium sensitivity