Regulation of Muscle Contraction

The main feature of muscle contraction is the interaction of actin, myosin and ATP. This fundamental process of contraction is regulated by the tropomyosin-troponin-Ca2+ system. According to the current theory, in the resting muscle TM is positioned in the groove of the actin double helix in a way that it sterically blocks the combination of myosin with actin. This is illustrated in Fig. RE1a, which shows a thin filament composed of actin, tropomyosin, TN-C, TN-I, and TN-T.

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Fig. RE1a. The functional unit of the thin filament in relaxed (A) and Ca2+-activated states (B). (Courtesy of Dr. Helen Rarick).

In the absence of Ca2+ (Relaxed state), TM blocks the cross-bridge binding sites on actin. Binding of Ca2+ to TN-C (Activated state) initiates the TM movement, through TN-T, from the center of the actin strand to its side, thereby releasing the steric blocking. In addition, the TN-C-Ca2+ complex removes TN-I from its inhibitory position on actin; thus the combination of the myosin head with actin can proceed to full extent (see Fig. H4). Since in the thin filament there is only one TN and one TM molecule per seven G-actin molecules, one has to assume that cooperative interactions play a major role in the regulation of contraction.

Lehman and collaborators (1994) provided evidence for a TM based steric mechanism in Limulus thin filaments (Figs. RE2 and RE3). Further experiments with frog skeletal muscle confirmed the steric-model for activation of muscle thin filaments (Vibert et al., 1997). Recently, by using cryoelectron microscopy and helical image reconsruction the location of tropomyosin in troponin regulated thin filaments has been resolved under both relaxing and activating conditions (Xu et al., 1999).

Fig. RE2. Ca -induced tropomyosin movements in Limulus thin filaments revealed by three-dimensional reconstruction of electron micrographs. (From Lehman et al., 1994). Photographer, M. Picard Craig, Reproduced with permission from Nature 368, 65-67, 1994 (http://www.nature.com).

Fig. RE3. Density maps of the strands, shown in

Fig. RE2.(From Lehman et al., 1994). Photographer, M. Picard Craig, Reproduced with permission from Nature 368, 65-67, 1994 (http://www.nature.com).

Fig. RE3. Density maps of the strands, shown in

Fig. RE2.(From Lehman et al., 1994). Photographer, M. Picard Craig, Reproduced with permission from Nature 368, 65-67, 1994 (http://www.nature.com).

Picture on Fig. RE2 shows surface views of reconstructed densities of thin filaments, left in the presence of EGTA (a strong Ca2+ complexing agent, thus in the presence of EGTA there is practically no free Ca2+), right in the presence of Ca2+. The helically wound strands on the surface of actin have a diameter of about 20 A (that is the width of TM). The inner (Ai) and outer (Ao) domains of one actin monomer are marked. The actin monomer shapes from both the EGTA- and Ca2+-treated filaments are very similar, but the elongated strands of density originating from TM are located in different positions on the actin filaments. Fig. RE3 shows helical projections formed by projecting the map densities of RE2 onto a plane perpendicular to the helix axis, a) thin filaments in EGTA, b) thin filaments in Ca2+. The TM strand, which makes contact with actin monomers at A0 and Ai in a) and b), respectively, is indicated by arrows. The difference map in c) was calculated by subtracting densities in the Ca2+ map from those in the EGTA map. The regions of the maps that are significantly different are indicated by white (positive differences) and by black (negative differences). The pairs of positive and negative peaks are located at the respective strand positions and demonstrate strand movement.

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