Cardiac Excitation-Contraction Coupling

Overview

Cardiac Excitation-Contraction Coupling describes the molecular mechanisms by which the cardiac action potential initiates physical contraction of the cardiomyocyte. Excitation-Contraction Coupling within Cardiomyocytes is largely similar to that observed in Skeletal Muscle with some important differences as described below.

Molecular Mechanism

Overall, the membrane depolarization during the cardiac action potential initiates a large influx of calcium ions into the cardiomyocyte cytosol. This spike in intracellular calcium concentration is the signal which initiates physical shortening of actin-myosin fibrils within the cell. Coordinated shortening of actin-myosin fibrils manifests as physical contraction of the cardiomyocyte.

As described in the Cardiac Action Potential - Cellular Basis, the action potential results in rapid depolarization of the cardiomyocyte membrane potential. This depolarization is transmitted to the interior of the cell by specialized, tubular invaginations of the membrane termed T-tubules.

Depolarization of the T-tubules results in release of calcium ions stored within the cardiomyocyte sarcoplasmic reticulum. However, unlike skeletal muscle myocytes, the sarcoplasmic reticulum of cardiomyocytes is not very extensive and does not provide a sufficient store of calcium ions. Instead, a sizable proportion of calcium enters the cardiomyocytes through L-type calcium channels on the cardiomyocyte membrane during the unique, Plateau Phase of the cardiac action potential. Consequently, a critical portion of calcium entering cardiomyocytes following depolarization is derived from an extracellular source.

The molecular basis of tension in all contractile cells is the interaction of actin and myosin fibrils. When these fibrils are allowed to interact, myosin fibers physically crawl along the actin fibrils. Because actin fibrils are ultimately anchored to the cell membrane, this crawling action results in physical shortening and thus contraction of the cell. In the resting state, actin and Myosin fibrils are prevented from interacting by the filamentous protein tropomyosin which wraps around actin fibrils and blocks myosin head groups from interacting with actin. The capacity of tropomyosin to wrap actin is regulated by troponin. Troponin is itself regulated by calcium, and when cytosolic calcium concentrations are high, troponin removes tropomyosin from the actin fibril, thus allowing actin-myosin interaction to take place. Consequently, the presence of intracellular calcium is connected to tension-generation through its capacity to modulate troponin and tropomyosin and thus regulate access of myosin to actin.

Following the repolarization phase of the cardiac action potential, intracellular calcium is rapidly effluxed from the cytosol either into the sarcoplasmic reticulum or into the extracellular fluid. Once intracellular calcium concentrations drop, Troponin once again allows tropomyosin to wrap actin, blocking myosin interaction, thus reducing tension within cardiomyocytes. Macroscopically, this manifests as a relaxation of the myocardium.

Regulation

An essential property of cardiomyocytes is that the quantity of tension the cells produce once depolarized is subject to regulation. This feature of cardiomyocytes plays a critical role in the macroscopic physiology of the heart. Two basic factors affect cardiomyocyte tension generation: 1) The quantity of intracellular calcium following depolarization, and 2) The starting length of the cardiomyocyte

The amount of tension generated by cardiomyocytes following depolarization is directly related to the intracellular calcium concentration. As described above, a significant proportion of calcium enters cardiomyocytes from L-type calcium channels during the Plateau Phase of the cardiac action potential. Because the length of the Plateau Phase can be modulated by autonomic cardiac regulation, the peak concentration of intracellular calcium can be regulated, thus allowing control over the amount of tension generated within the cell.

As the cardiomyocyte is stretched, the degree of overlap between actin and myosin fibrils changes and this affects how much tension these fibrils can generate once calcium influx has occurred. In general, as the cardiomyocyte is stretched from short lengths, the degree of actin-myosin overlap increases, allowing proportionally more tension generation. However, after a certain threshold, further stretch begins to reduce actin-myosin overlap, and tension generation falls with further stretching. This relationship between stretch and tension generation is thought to be the molecular basis of the macroscopically-observable Frank-Starling Relationship

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