Cardiac thin filament regulation

Abstract

Myocardial contraction is initiated upon the release of calcium into the cytosol from the sarcoplasmic reticulum following membrane depolarization. The fundamental physiological role of the heart is to pump an amount blood that is determined by the prevailing requirements of the body. The physiological control systems employed to accomplish this task include regulation of heart rate, the amount of calcium release, and the response of the cardiac myofilaments to activator calcium ions. Thin filament activation and relaxation dynamics has emerged as a pivotal regulatory system tuning myofilament function to the beat-to-beat regulation of cardiac output. Maladaptation of thin filament dynamics, in addition to dysfunctional calcium cycling, is now recognized as an important cellular mechanism causing reduced cardiac pump function in a variety of cardiac diseases. Here, we review current knowledge regarding protein-protein interactions involved in the dynamics of thin filament activation and relaxation and the regulation of these processes by protein kinase-mediated phosphorylation.

Fig. 1

a Schematic diagram illustrating protein components of the cardiac sarcomere with a specific emphasis on the thin filament. The top panels illustrate the sarcomere in the resting condition in the absence of calcium bound to troponin C (cTnC, red). In this condition, troponin I (cTnI, green) acts to inhibit myosin cross-bridge formation (thick filament, purple) to actin (gray) via troponin T (cTnT, blue) and tropomyosin (orange). Binding of Ca²⁺ to cTnC (bottom panels) relieves this inhibition and allows movement of tropomyosin to the outer domain of the actin filament, thus exposing myosin-binding sites on actin. The right panels illustrate in greater detail the molecular protein–protein interactions in the cardiac troponin complex upon Ca²⁺ activation. b Estimated structure of the troponin complex (TnC, blue; TnI, pink; TnT, yellow), the tropomyosin strand (green), and actin filament (brown) in the Ca²⁺-free diastolic state (top panel) and Ca²⁺-bound systolic state (bottom panel). The approximate position of the inhibitory region of TnI is indicated in the top panel by the white arrow. The structure and relative positions employed to construct these projections are based on data obtained for rabbit skeletal muscle (actin) and bovine cardiac muscle (troponin and tropomyosin) by the Lehman group using electron microscopy data and helical and single particle reconstruction [55, 56]