Tm

Myosin binding site

(c) Skeletal muscle CONTRACTION

Ca2+T

Ca2+T

▲ FIGURE 19-24 Actin-dependent regulation of skeletal muscle contraction. (a) Model of the tropomyosin-troponin (TM-TN) regulatory complex on a thin filament. TN, a clublike complex of TN-C, TN-I, and TN-T subunits, is bound to the long a-helical TM molecule. (b) Three-dimensional electron-microscopic reconstructions of the TM helix (yellow) on a thin filament from scallop muscle. TM in its "off" state (left)

shifts to its new position (arrow) in the "on" state (right) when the Ca2+ concentration increases. This movement exposes myosin-binding sites (red) on actin. TN is not shown in this representation. (c) Regulation of skeletal muscle contraction by Ca2+ binding to TN. Note that the TM-TN complex remains bound to the thin filament whether muscle is relaxed or contracted. [Part (b) adapted from W. Lehman, R. Craig, and P Vibert, 1993, Nature 123:313; courtesy of P Vibert.]

low cytosolic Ca2+ level is maintained primarily by a unique Ca2+ ATPase that continually pumps Ca2+ ions from the cytosol into the sarcoplasmic reticulum (SR), a specialized endoplasmic reticulum in the muscle-cell cytosol (see Figure 7-7). This activity establishes a reservoir of Ca2+ in the SR.

The arrival of a nerve impulse at a neuromuscular junction leads to the opening of voltage-gated Ca2+ channels in the SR membrane (see Figure 7-45). The ensuing release of Ca2+ from the SR raises the cytosolic Ca + concentration surrounding myofibrils sufficiently to trigger contraction. In skeletal muscle, the cytosolic Ca2+ concentration influences the interaction of four accessory proteins with actin thin filaments. The position of these proteins on the thin filaments in turn controls myosin-actin interactions.

Tropomyosin (TM) is a ropelike molecule, about 40 nm in length; TM molecules are strung together head to tail, forming a continuous chain along each actin thin filament (Figure 19-24a). Associated with tropomyosin is troponin (TN), a complex of the three subunits, TN-T, TN-I, and TN-C. Troponin-C is the calcium-binding subunit of troponin. Similar in sequence to calmodulin and the myosin light chains, TN-C controls the position of TM on the surface of an actin filament through the TN-I and TN-T subunits.

Scientists currently think that, under the control of Ca2 + and TN, TM can occupy two positions on a thin filament— an "off" state and an "on" state. In the absence of Ca2+ (the off state), myosin can bind to a thin filament, but the TM-TN complex prevents myosin from sliding along the thin filament. Binding of Ca2+ ions to TN-C triggers a slight movement of TM that exposes the myosin-binding sites on actin (Figure 19-24b). At Ca2+ concentrations > 10—6 M, the inhibition exerted by the TM-TN complex is relieved, and con traction occurs. The Ca2+-dependent cycling between on and off states in skeletal muscle is summarized in Figure 19-24c.

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