In striated muscle, the
protein troponin complex turns contraction on and off in a
calcium-dependent manner. The
calcium-sensing component of the complex is
troponin C, which is expressed from the TNNC1 gene in both cardiac muscle and slow-twitch skeletal muscle (identical transcript in both tissues) and the TNNC2 gene in fast-twitch skeletal muscle. Cardiac
troponin C (cTnC) is made up of two globular EF-hand domains connected by a flexible linker. The structural C-domain (cCTnC) contains two high affinity
calcium-binding sites that are always occupied by Ca(2+) or Mg(2+) under physiologic conditions, stabilizing an open conformation that remains anchored to the rest of the
troponin complex. In contrast, the regulatory N-domain (cNTnC) contains a single low affinity site that is largely unoccupied at resting
calcium concentrations. During muscle activation,
calcium binding to cNTnC favors an open conformation that binds to the switch region of
troponin I, removing adjacent inhibitory regions of
troponin I from actin and allowing muscle contraction to proceed. Regulation of the
calcium binding affinity of cNTnC is physiologically important, because it directly impacts the
calcium sensitivity of muscle contraction.
Calcium sensitivity can be modified by drugs that stabilize the open form of cNTnC, post-translational modifications like phosphorylation of
troponin I, or downstream thin filament
protein interactions that impact the availability of the
troponin I switch region. Recently, mutations in cTnC have been associated with hypertrophic or
dilated cardiomyopathy. A detailed understanding of how
calcium sensitivity is regulated through the
troponin complex is necessary for explaining how mutations perturb its function to promote
cardiomyopathy and how post-translational modifications in the thin filament affect heart function and
heart failure.
Troponin modulating drugs are being developed for the treatment of
cardiomyopathies and
heart failure.