Excitation-Contraction Coupling Muscle action potentials trigger mechanical contraction through a process called excitationcontraction coupling, which is illustrated

in Figure 27. The major event of excitationcontraction coupling is a dramatic rise in the intracellular free Ca2+ concentration. The "resting" intracellular free Ca2+ concentration is less than 0.1 M. In contrast, during maximum activation of the contractile apparatus, the intracellular free Ca2+ concentration reaches nearly 100 M. When the wave of depolarization passes over the muscle cell membrane and down the T tubules, Ca2+ is released from the SR into the intracellular fluid.

As indicated on the left side of Figure 27, the specific trigger for this release appears to be the entry of calcium into the cell via the L-type calcium channels and an increase in Ca2+ concentration in the region just under the sarcolemma on the surface of the cell and throughout the t-tubular system. Unlike skeletal muscle, this highly localized increase in calcium is essential for triggering the massive release of calcium from the SR. This calcium induced calcium release is a result of opening calcium-sensitive release channels on the SR.7 Although the amount of Ca2+ that enters the cell during a single action potential is quite small compared with that released from the SR, it is not only essential for triggering the SR calcium release but also essential for maintaining adequate levels of Ca2+ in the intracellular stores over the long run.

When the intracellular Ca2+ level is high (>1.0 M), links called cross-bridges form between two types of filaments found within muscle. Sarcomere units, as depicted in the lower part of Figure 27, are joined end to end at Z lines to form myofibrils, which run the length of the muscle cell. During contraction, thick and thin filaments slide past one another to shorten each sarcomere and thus the muscle as a whole. The bridges form when the regularly spaced myosin heads from thick filaments attach to regularly spaced sites on the actin molecules in the thin filaments. Subsequent deformation of the bridges result in a pulling of the actin molecules toward the center of the sarcomere. This actin-myosin interaction requires energy from ATP. In resting muscles, the attachment of myosin to the actin sites is inhibited by troponin and tropomyosin. Calcium causes muscle contraction by interacting with troponin C to cause a configurational change that removes the inhibition of the actin sites on the thin filament. Since a single cross-bridge is a very short structure, gross muscle shortening requires that cross-bridges repetitively form, produce incremental movement between the myofilaments, detach, form again at a new actin site, and so on, in a cyclic manner. There are several processes that participate in the reduction of intracellular Ca2+ that terminates the contraction. These processes are illustrated on the right side of Figure 27. Approximately 80% of the calcium is actively taken back up into the SR by the action of Ca2+-ATPase pumps located in the network part of the SR.8 About 20% of the calcium is extruded from the cell into the extracellular fluid either via the Na+-Ca2+ exchanger located in the sarcolemma9 or via sarcolemmal Ca2+-ATPase pumps. Excitation-contraction coupling in cardiac muscle is different from that in skeletal muscle in that it may be modulated; different intensities of actin-myosin interaction (contraction) can result from a single action potential trigger in cardiac muscle. The mechanism for this seems to be dependent on variations in the amount of Ca2+ reaching the myofilaments and therefore the number of cross-bridges activated during the twitch. This ability of cardiac muscle to vary its contractile strengthie, change its contractilityis extremely important to cardiac function, as will be discussed in a later section of this chapter. The duration of the cardiac muscle cell contraction is approximately the same as that of its action potential. Therefore, the electrical refractory period of a cardiac muscle cell is not over until the mechanical response is completed. As a consequence, heart muscle cells cannot be activated rapidly enough to cause a fused (tetanic) state of prolonged contraction. This is fortunate because intermittent contraction and relaxation are essential for the heart's pumping action. 7 These channels may be blocked by the plant alkaloid ryanodine and are activated by the methylxanthine caffeine. These agents are chemical tools used to assess properties of these SR channels. 8 The action of these pumps is regulated by the protein phospholamban. When this protein is phosphorylated (for example, by the action of norepinephrine) the rate of Ca2+ resequestration is increased and the rate of relaxation is enhanced. 9 The Na+-Ca2+ exchanger is powered by the sodium gradient across the sarcolemma which in turn is maintained by the Na+/K+ ATPase. This exchanger is electrogenic in that three Na+ ions move into the cell in exchange for each Ca2+ ion that moves out. This net inward

movement of positive charge may contribute to the maintenance of the plateau phase of the action potential. The cardiac glycoside, digitalis, slows down the Na+/K+ pump and thus reduces the sodium gradient which in turn results in an increase in intracellular Ca2+. This mechanism contributes to the positive effect of cardiac glycosides on the contractile force of the failing heart.