Biochemical Interactions Of Actin And Myosin

Smooth muscle myosin is also an adenosine triphos-phatase (ATPase), and energy is required for muscle contraction. Like skeletal muscle myosin, pure smooth muscle myosin exhibits little ATPase activity. Unlike skeletal muscle myosin, smooth muscle myosin ATPase activity is not increased upon addition of actin alone, unless one set of the myosin light chains is phosphory-lated. In smooth muscle cells, adenosine triphosphate (ATP) hydrolysis due to the cycling of phosphorylated myosin crossbridges with actin is thought to be similar to what occurs in striated muscle cells (see Chapter 7).

Regulation of smooth muscle contraction is mediated via the thick filaments rather than via the thin filaments. Tropomyosin is present in smooth muscle and is thought to reside on the thin filaments; however, there is little or no troponin complex. Thus, regulatory mechanisms must differ from those seen in striated muscle (Fig. 2). The main mechanism appears to involve phosphorylation of the 20,000-Da light chains of myosin. In resting smooth muscle, phosphorylation is low. Myosin light-chain kinase is the enzyme that, on stimulation, is activated and quickly catalyzes the phosphorylation of the myosin light chains. This results in actin-activated ATPase activity and contraction. When the stimulus to contract ceases, kinase activity decreases, myosin light chains are dephosphorylated by phosphatases, and the muscle relaxes. Although the regulatory proteins are different in smooth muscle, the sequence of events leading to contraction is due to the actions of calcium.

Pivotal Role of Calcium

As in striated muscle, contraction and relaxation of smooth muscle are regulated by changes in the amount of cytosolic calcium available to interact with the regulatory protein. In relaxed muscle, the level of free

A Smooth muscle

Calmodulin

B Striated muscle

^ Light chain kinase

Myosin

Phosphatase Myosin ~P + actin

-Contraction

Contraction

Tropomyosin Troponin : Ca

Ca2+

Troponin

Tropomyosin

Actin

FIGURE 2 (A) Pathways for calcium regulation of contraction in smooth muscle. (B) Pathways for calcium regulation in striated muscle.

cytosolic calcium (calcium that is not bound to other structures such as sarcoplasmic reticulum [SR], mitochondria, and nuclei) is low (<10—7 M). Upon stimulation of the muscle, the level increases into the micromolar, or higher, range to initiate contraction. Calcium binds first with calmodulin (one of the calcium-binding proteins found in many tissues), and then the calcium-calmodulin complex binds to and activates the myosin light-chain kinase. Once the stimulus for muscle contraction ceases, free calcium levels decrease, and calcium dissociates from the regulatory proteins. The muscle then relaxes.

The sources and sinks for calcium (and, therefore, excitation-contraction coupling) vary markedly from one smooth muscle to another (Fig. 3). Some have an abundant SR. When these cells are excited, events initiated at the cell membrane cause the release of calcium from the SR. The manner in which this release comes about is not clear; however, at least two

Cytoplasm

FIGURE 3 Intracellular free calcium levels are the result of (1) the influx and efflux of Ca2+ from the extracellular fluid, (2) the release and reuptake of Ca2+ from the sarcoplasmic reticulum (SR), and, perhaps, (3) the release and reuptake of Ca2+ from the mitochondria.

Cytoplasm

FIGURE 3 Intracellular free calcium levels are the result of (1) the influx and efflux of Ca2+ from the extracellular fluid, (2) the release and reuptake of Ca2+ from the sarcoplasmic reticulum (SR), and, perhaps, (3) the release and reuptake of Ca2+ from the mitochondria.

mechanisms have been demonstrated. During excitation of the cell membrane, an influx of small amounts of extracellular calcium through calcium channels may trigger the release of the internal stores. Additionally, receptor activation by ligands may stimulate the intra-cellular production of second messengers, such as inositol trisphosphate, which in turn cause the release of SR calcium. Other smooth muscle cells have almost no SR; these cells must rely on the entry of enough calcium through membrane calcium channels to activate their contractile proteins.

As in striated muscle, cytoplasmic free calcium must be decreased to allow for relaxation. In those cells with abundant SR, most of this calcium is pumped back into the SR via a calcium ATPase. However, in these cells, and especially in those cells with little SR, calcium must also be expelled from the cell across the cell membrane. Presumably, this is accomplished by a sodium-calcium exchange mechanism and perhaps by a membrane-bound calcium ATPase.

No smooth muscle has as well developed an SR as that seen in striated muscle. Thus, as in cardiac muscle, not enough calcium is normally present within smooth muscle cells to activate fully the contractile proteins. As in cardiac muscle, smooth muscles rely to varying degrees on an influx of extracellular calcium for contraction. During steady-state conditions, influx will be matched by efflux. However, as in cardiac muscle, varying rates of influx and efflux make it possible for there to be moment-to-moment net gains and losses of calcium available to initiate contraction.

Excitation of the Muscle Cell

Smooth muscles vary in the electrical events exhibited by their cell membranes. During relaxation, all are polarized, exhibiting resting membrane potentials of —40 to —80 mV. The basis for this potential is primarily the same as in striated muscle (Fig. 4). In many smooth muscles the membrane potential in relaxed cells is not stable. For example, in intestinal smooth muscle, cyclic depolarizations and repolarizations of 10 to 15 mV occur regularly (Fig. 5). The importance of these fluctuations is discussed in Chapter 33. Although different types of smooth muscle differ only slightly in resting potential, they differ markedly from one another and from striated muscle in the types of potentials exhibited when they are excited (Fig. 6). Most smooth muscles appear to have sarcolemmal calcium channels that open upon stimulation of the cell. Many of these are voltage dependent, like those in cardiac muscle. However, some cells have calcium channels that are activated not by voltage changes but by the combination of a ligand with its receptor on the cell surface or by

FIGURE 4 Schematic of the ionic events that may be responsible for the resting membrane potential in smooth muscle. The shaded horizontal bar indicates the cell membrane. The direction of the arrows indicates the direction of the movement, and the thickness of the arrows indicates the relative permeabilities. The coupling between Na+ and K+ indicates an active transport. The role of Cl is not understood, as indicated by the question marks.

FIGURE 4 Schematic of the ionic events that may be responsible for the resting membrane potential in smooth muscle. The shaded horizontal bar indicates the cell membrane. The direction of the arrows indicates the direction of the movement, and the thickness of the arrows indicates the relative permeabilities. The coupling between Na+ and K+ indicates an active transport. The role of Cl is not understood, as indicated by the question marks.

FIGURE 5 Electrical (mV) and contractile (Gm, where Gm indicates that the force is measured in grams) activities of intestinal smooth muscle. The muscle exhibits spontaneous slow depolarizations and repolarizations of membrane potential that cause little change in force.

FIGURE 5 Electrical (mV) and contractile (Gm, where Gm indicates that the force is measured in grams) activities of intestinal smooth muscle. The muscle exhibits spontaneous slow depolarizations and repolarizations of membrane potential that cause little change in force.

FIGURE 6 Electrical (mV) and contractile (Gm, where Gm indicates that the force is measured in grams) activities of two different smooth muscles. (A) One muscle exhibits stepwise depolarizations and repolarizations that cause increases and decreases in force, respectively. (B) The other muscle exhibits rapid transients that arise from a more stable baseline potential. These transients can occur alone or in bursts such that they induce a muscle twitch, summation, or tetany.

FIGURE 6 Electrical (mV) and contractile (Gm, where Gm indicates that the force is measured in grams) activities of two different smooth muscles. (A) One muscle exhibits stepwise depolarizations and repolarizations that cause increases and decreases in force, respectively. (B) The other muscle exhibits rapid transients that arise from a more stable baseline potential. These transients can occur alone or in bursts such that they induce a muscle twitch, summation, or tetany.

stretch of the membrane. Action potentials do not occur in all cells that are activated by ligand-receptor interaction or stretch. In these cells, calcium influx may be matched by an efflux of potassium, resulting in small, or no, changes in membrane potential.

Smooth muscle cells also vary in the manner in which they are excited. As stated above, many have membrane

FIGURE 7 Schematic of three smooth muscle cells that are connected by gap junctions. The dashed lines indicate the pathways and spread of excitation.

potentials that fluctuate rhythmically to periodically reach threshold levels. Others have stable resting potentials. Most can respond to neurotransmitters, hormones, or other ligands that combine with membrane receptors, and many can even respond to mechanical stimuli such as stretch. Each particular type of smooth muscle usually will exhibit one of these behaviors to a higher degree. Examples of each type are found in those chapters that deal with specific organs such as the intestine, uterus, and blood vessels.

Smooth muscle cells differ in their degrees of coupling to one another. In some organs, such as the intestine, membranes of adjacent smooth muscle cells make intimate contact with one another so that low-resistance electrical pathways exist (Fig. 7). Thus, excitation of one cell quickly will spread and a group of cells will contract in unison. Such muscle is referred to as unitary smooth muscle. In other organs, such as the vas deferens, no such intercellular pathways exist, and each cell must be excited individually. Such muscle is referred to as multiunit smooth muscle (Fig. 8).

Smooth muscle cells lack well-developed transverse (T) tubules. Some have pockmarked indentations of their membrane and collections of SR vesicles just under the membrane, but these lack the structure of the T

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