The contraction of muscles from all sources occurs by the general mechanism described earlier. However, the manner in which contraction is regulated differs among the various types of muscle tissue. Striated muscle relies on actin-based regulation, while regulation in smooth muscle is myosin-based. However, regardless of whether regulation is actin- or myosin based, the second messenger Ca2+ plays a central role in the initiation and control of contraction.

Actin-Based Regulation Occurs in Skeletal Muscle

The contractile apparatus in skeletal muscle is regulated by the troponin system, which is bound to tropomyosin and F-actin in the thin filament. In resting muscle, TpI prevents binding of the myosin head to its F-actin attachment site either by altering the conformation of F-actin via the tropomyosin molecules or by simply rolling tropomyosin into a position that directly blocks the sites on F-actin to which the myosin heads attach. Binding of Ca2+ to TpC relieves inhibition by TpI, permitting the power stroke cycle to proceed. When Ca2+levels fall, the TpC:Ca2+ complex dissociates, allowing TpI to reestablish its inhibitory block on the binding of the myosin S-1 head to F-actin. The thick and thin filaments detach from one another, allowing the muscle to relax.

Myosin-Based Regulation Occurs in Smooth Muscle

Unlike skeletal muscle, smooth muscles contract along multiple axes. Thus, although they have molecular structures similar to those in striated muscle, they lack striations because their sarcomeres are not aligned. Smooth muscles contain α-actinin and tropomyosin molecules, as do skeletal muscles, but they lack the troponin system. In smooth muscle, it is the light chains that prevent the binding of the myosin head to F-actin in the resting state. This inhibitory block is released by the phosphorylation of the regulatory, or type 2, light chains in the myosin S-1 head by myosin light-chain kinase. The activity of myosin light-chain kinase is controlled by the binding of calmodulin (Figure 1).

Fig1. Regulation of smooth muscle contraction by Ca2+. The pL-myosin is the phosphorylated light chain of myosin and L-myosin is the dephosphorylated light chain.

Calmodulin is a small, (≈ 17 kDa), ubiquitous protein that contains four EF-hand motifs, each of which can bind one molecule of calcium. Binding of calcium to all four of these sites triggers a conformational change that enables the (Ca2+)4 :calmodulin complex to bind to and activate various intracellular target enzymes, including myosin light-chain kinase and Ca2+-ATPase (see later). Ca2+ binding to calmodulin exhibits strong positive cooperativity, enabling calmodulin to act as a Ca2+-sensitive molecular trigger. When Ca2+ levels fall, the balance of activity between myosin light-chain kinases and phosphatases shifts in favor of the latter, leading to the dephosphorylation of regulatory light chains, the detachment of myosin S-1 domains from actin, and muscle relaxation.

Rho kinase provides a Ca2+-independent pathway for initiating contraction. Rho kinase phosphorylates myosin’s regulatory light chains, as well as phosphorylating the phosphatase that dephosphorylates the light chains. Since phosphorylation of the phosphatase inhibits its activity, this further shifts the balance between the kinases and phosphatases that act on myosin in favor of the former. Table 1 summarizes and compares the regulation of actin-myosin interactions (activation of myosin ATPase) in striated and smooth muscles. Phosphorylation of Rho kinase by the cAMP-dependent protein kinase may play a role in the dampening effect of this second messenger on smooth muscle contraction.

Table1. Actin-Myosin Interactions in Striated & Smooth Muscle

Caldesmon (87 kDa), another regulatory protein, is ubiquitous in smooth muscle and also present in nonmuscle tissue.

At low [Ca2+], caldesmon binds to tropomyosin and actin, pre venting the interaction of actin with myosin, thereby keeping muscle in a relaxed state. At higher [Ca2+], (Ca2+)4 :calmodulin binds caldesmon, releasing it from actin. Now actin is free to bind myosin and contraction can occur. Caldesmon is also subject to covalent modification by phosphorylation dephosphorylation; when phosphorylated, it cannot bind actin, again freeing the latter to interact with myosin.

The Sarcoplasmic Reticulum Regulates Intracellular Levels of Ca2+ in Skeletal Muscle

When striated muscle is in the relaxed state, the Ca2+ needed to initiate contraction is kept stored, ready for release into the sarcoplasm, in the sarcoplasmic reticulum (SR), a network of fibrous sacks. The SR is linked to the sarcomeres by the transverse channels of the T-tubule system. In resting muscle, the [Ca2+] in the sarcoplasm typically ranges between 10⁻⁸ and 10⁻⁷ mol/L. This low resting concentration is maintained by the basal activity of the Ca2+ ATPase (Figure 2), a Ca2+ activated calcium pump that uses the energy of hydrolysis of ATP to move calcium ions from regions of low to high concentration. Once inside the SR, Ca2+ is bound by calsequestrin, a specific Ca2+-binding protein.

Fig2. Diagram of the relationships among the sarcolemma (plasma membrane), a T tubule, and two cisternae of the SR of skeletal muscle (not to scale). The T tubule extends inward from the sarcolemma. A wave of depolarization, initiated by a nerve impulse, is transmitted from the sarcolemma down the T tubule. It is then conveyed to the Ca2+ release channel (RYR), perhaps by interaction between it and the dihydropyridine receptor (slow Ca2+ voltage channel), which lie in proximity to one other. Release of Ca2+ from the Ca2+ release channel into the cytosol initiates contraction. Subsequently, Ca2+ is pumped back into the cisternae of the SR by the Ca2+ ATPase (Ca2+ pump) and stored there, in part bound to calsequestrin.

On release of Ca2+ into the sarcoplasm, (Ca2+)4 :calmodulin binds to and activates the Ca2+-dependent ATPase. This immediately sets into motion the export of Ca2+ from the sarcoplasm back into the SR, enabling the muscle to rapidly relax and ready for future contraction. If the concentration of ATP in the sarcoplasm falls dramatically (eg, by excessive usage during the cycle of contraction-relaxation or by diminished formation, such as might occur in ischemia), the Ca2+-ATPase will cease pumping and calcium ion levels will remain high.

When the sarcolemma is excited by a nerve impulse, the excitable membranes of the T-tubule system become depolarized, opening the voltage-gated Ca2+ release channels (homo tetramer, ≈565 kDa per subunit) in the nearby SR. Ca2+ rapidly floods into the sarcoplasm, raising the concentration nearly 100-fold, to 10⁻⁵ mol/L, where it binds to troponin C and calmodulin to initiate contraction. Ryanodine, a plant alkaloid, binds to and modulates the activity a voltage-gated Ca2+ channel also known as the ryanodine receptor (RYR). The two isoforms, RYR1 and RYR2, present in skeletal muscle and heart muscle, respectively. RYR2 is also present in brain tis sue. RYR is in the proximity of the dihydropyridine receptor, a voltage-gated Ca2+ channel of the transverse tubule system, (see Figure 2).

Mutations in the Gene Encoding the Ca2+ Release Channel Are Cause of Human Malignant Hyperthermia

Exposure to certain anesthetics (eg, halothane) and depolarizing skeletal muscle relaxants (eg, succinylcholine) can cause malignant hyperthermia (MH) in some genetically predisposed patients. Symptoms of MH include rigid skeletal muscles, hypermetabolism, and high fever. To prevent other complications or death, anesthetic is stopped immediately and the drug dantrolene is administered. Dantrolene is a skeletal muscle relaxant that acts to inhibit release of Ca2+ from the SR into the cytosol.

The causes of MH in humans may involve mutations in the genes encoding the Ca2+ release channel, calsequestrin-1, the dihydropyridine receptor, or in the RYR receptor that foster high cytosolic Ca2+ levels. Mutations in the RYR1 gene are also associated with central core disease. This is a rare myopathy presenting in infancy with hypotonia and proximal muscle weakness. Electron microscopy reveals an absence of mitochondria in the center of many type I muscle fibers. Damage to mitochondria induced by high intracellular levels of Ca2+ secondary to abnormal functioning of RYR1 appears to be responsible for the morphologic findings.

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