Smooth Muscle

Smooth muscle is responsible for the contractility of hollow organs, such as blood vessels, the gastrointestinal tract, the bladder, or the uterus. Its structure differs greatly from that of skeletal muscle, although it can develop isometric force per cross-sectional area that is equal to that of skeletal muscle. However, the speed of smooth muscle contraction is only a small fraction of that of skeletal muscle.

Structure: The most striking feature of smooth muscle is the lack of visible cross striations (hence the name smooth). Smooth muscle fibers are much smaller (2-10 ^ in diameter) than skeletal muscle fibers (10-100 ^ ). It is customary to classify smooth muscle as single-unit and multi-unit smooth muscle (Fig. SM1). The fibers are assembled in different ways. The muscle fibers making up the single-unit muscle are gathered into dense sheets or bands. Though the fibers run roughly parallel, they are densely and irregularly packed together, most often so that the narrower portion of one fiber lies against the wider portion of its neighbor. These fibers have connections, the plasma membranes of two neighboring fibers form gap junctions that act as low resistance pathway for the rapid spread of electrical signals throughout the tissue. The multi-unit smooth muscle fibers have no interconnecting bridges. They are mingled with connective tissue fibers.

Electron micrographs of smooth muscle reveal that the actin filaments are organized through attachment to the dense bodies that contain a-actinin, a Z-band protein in skeletal muscle. Thus, it is assumed that the dense bodies function as Z-lines. The ratio of thin to thick filaments is much higher in smooth muscle (~15:1) than in skeletal muscle (~6:1). Smooth muscle is rich in intermediate filaments that contain two specific proteins, desmin and vimentin.

Innervation and stimulation: Smooth muscle is primarily under the control of autonomic nervous system, whereas skeletal muscle is under the control of the somatic nervous system. The single-unit smooth muscle has pacemaker regions where contractions are spontaneously and rhythmically generated. The fibers contract in unison, that is the single unit of smooth muscle is syncytial. The fibers of multi-unit smooth muscle are innervated by sympathetic and parasympathetic nerve fibers and respond independently from each other upon nerve stimulation.

Nerve stimulation in smooth muscle causes membrane depolarization, like in skeletal muscle. Excitation, the electrochemical event occurring at the membrane is followed by the mechanical event, contraction. In the case of smooth muscle, this excitation-contraction coupling is termed electromechanical coupling; the link for the coupling is Ca2+ that permeates from the extracellular space into the intracellular water of smooth muscle. There is another excitation mechanism in smooth muscle, which is independent of the membrane potential change; it is based on receptor activation by drugs or hormones followed by muscle contraction. This is termed pharmacomechanical coupling. The link is Ca2+ that is released from an internal source, the sarcoplasmic reticulum.

The role of mechanical events of smooth muscle in the wall of hollow organs is twofold: 1) Its tonic contraction maintains organ dimensions against imposed load. 2) Force development and muscle shortening, like in skeletal muscle.

Myofibril proteins: In general, smooth muscle contains much less protein (~110 mg/g muscle) than skeletal muscle (~200 mg/g). Notable is the decreased myosin content, ~20 mg/g in smooth muscle versus ~80 mg/g in skeletal muscle. On the other hand, the amounts of actin and tropomyosin are the same in both types of muscle. Smooth muscle does not contain troponin, instead of it there are two other thin filament proteins, caldesmon and calponin.

The amino acid sequence of smooth muscle actin is very similar to that of its skeletal muscle counterpart, and it seems likely that their three-dimensional structures are also similar. Smooth muscle actin combines with either smooth or skeletal muscle myosin. However, there is a major difference in the activation of myosin ATPase by actin, smooth muscle myosin has to be phosphorylated for actin-activation to occur.

The size and shape of the smooth muscle myosin molecule is similar to that of the skeletal muscle myosin (Fig. M1). There is a small difference in the light chain composition; out of the four light chains of the smooth muscle myosin two have molecular weight of 20,000 and two of 17,000. The 20,000 light chain is phosphorylatable. Upon phosphorylation of the light chain the actin-activated smooth muscle myosin ATPase increases about 50-fold, to about 0.16 mol ATP hydrolyzed per mol of myosin head per sec, at physiological ionic strength and temperature. (Under the same conditions, the actin-activated skeletal muscle myosin ATPase is 10 -20 mol/mol/sec). The ionic strength dependence of smooth muscle myosin Ca2+-activated ATPase also differs from that of skeletal muscle myosin (Fig. M5), increasing ionic strength increases the smooth muscle myosin ATPase but decreases the skeletal muscle myosin ATPase.

Four smooth muscle specifc myosin heavy chain isoforms are known ( described in Quevillon-Cheruel et al., 1999). Two isoforms (named SMB and SMA) are defined by the presence or the absence of an insert of seven amino acids in the N-terminal globular head region. The two others (SM1 and SM2) differ at their C-termini by 43 versus 9 amino acids. To understand the role of the C-terminal extremities of SM1 and SM2 in smooth muscle thick filament assembly, various fragments of these myosins, such as the rod region, the rod with no tailpiece, or light meromyosins were prepared as recombinant proteins in bacterial cells (Rowner et al., 2001; Quevillon-Cheruel et al.,1999). The results showed that the smooth muscle myosin tailpieces differentially affect filament assembly and suggested that homogeneous thick filaments containing SM1 or SM2 myosin could serve distinct functions within smooth muscle cells.

Although the mechanism of thick filament assembly for purified smooth muscle myosins in vitro has been described, the regulation of thick filament formation in intact muscle is poorly understood. Cross-sectional density of the thick filaments measured electron microscopically in intact airway smooth muscle (Herrera et al., 2002) showed that the density increased substantially (144%) when the muscle was activated. In resting muscle, in the absence of Ca2+, the filament density decreased by 35%. It appears that in smooth muscle filamentous myosin exists in equilibrium with monomeric myosin; activation favors filament formation.

Kathleen Trybus pioneered in expressing and purifying smooth muscle myosin subfragments using the baculovirux /insect cell expression system. This procedure and the methods needed to characterize the new proteins (gel assays, ATPase activity determinations, transient state kinetic parameters, and the vitro motility assay) are described in her review (Trybus, 2000). Studies on engineered smooth muscle myosin and heavy meromyosin showed: the interaction between the regulatory light chain domains on two heads is critical for regulation of smooth muscle myosin (Li et al., 2000; Sweeney et al., 2000), a long, weakly charged actin-binding loop is required for phosphorylation-dependent regulation of smooth muscle myosin (Rovner, 1998), and coiled-coil unwinding at the smooth muscle myosin head-rod junction is required for optimal mechanical performance (Lauzon et al., 2001).

In vitro, both caldesmon and calponin are inhibiting the actin-activated ATPase activity of phosphorylated smooth muscle myosin. In case of calponin, this inhibitory activity is reversed by the binding of Ca2+-calmodulin or by phosphorylation. Calponin is a 34-kDa protein containing binding sites for actin, tropomyosin and Ca2+-calmodulin. Caldesmon is a long, flexible, 87-kDa protein containing binding sites for myosin, as well as actin, tropomyosin, and Ca2+-calmodulin. Electron microscopy and three-dimensional image reconstruction of isolated smooth muscle thin filaments revealed that calponin and caldesmon are located peripherally along the long-pitch actin helix (Hodgkinson et al., 1997; Lehman et al., 1997). The physiological role of caldesmon or calponin is not known.

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