Smooth muscles may contract in response to synaptic transmission or electrical coupling
Like skeletal muscle, smooth muscle receives synaptic input. However, the synaptic input to smooth muscle differs from that of skeletal muscle in two ways. First, the neurons are part of the autonomic nervous system rather than the somatic nervous system (see Chapter 14). Second, the neuron makes multiple synaptic contacts with a smooth-muscle cell in the form of a series of swellings called varicosities (see pp. 340–341) that contain the presynaptic machinery for vesicular release of transmitter. Each varicosity is close to the postsynaptic membrane of the smooth-muscle cell, but there is relatively little specialization of the postsynaptic membrane.
The mechanisms of intercellular communication between smooth-muscle cells vary more widely among tissues. There are two basic types of smooth-muscle tissues known as multiunit and single-unit smooth muscle. In multiunit smooth muscle, each smooth-muscle cell receives synaptic input but there is little intercellular electrical coupling between cells (i.e., few gap junctions). As a result, each smooth-muscle cell may contract independently of its neighbor. Thus, the term multiunit describes smooth muscle that behaves like multiple, independent cells or groups of cells (Fig. 9-13A). Multiunit smooth muscles are capable of fine control. Indeed, multiunit smooth muscle is found in the iris and ciliary body of the eye as well as the piloerector muscles of the skin.
FIGURE 9-13 Smooth-muscle organization. A, Multiunit. Each smooth-muscle cell receives its own synaptic input. B, Unitary. Only a few of the smooth-muscle cells receive direct synaptic input.
Unitary or single-unit smooth muscle (see Fig. 9-13B) is a group of cells that work as a syncytium because gap junctions provide electrical and chemical communication between neighboring cells. Direct electrical coupling allows coordinated contraction of many cells. Gap junctions also allow ions and small molecules to diffuse between cells, which gives rise to phenomena such as spreading Ca2+ waves among coupled cells. Unitary smooth muscle is the predominant smooth-muscle type within the walls of visceral organs such as the gastrointestinal and urinary tracts, the uterus, and many blood vessels. In certain organs, adjacent smooth-muscle cells are physically connected by adhering junctions that provide mechanical stability to the tissue. Thus, unitary smooth muscle is often referred to as visceral smooth muscle. The functional size of the unit depends on the strength of intercellular coupling. For example, in the bladder, extensive coupling among cells defines large functional units, which allows the cells of the muscular wall of the bladder to contract in synchrony. On the other hand, the smooth-muscle cells of blood vessels couple to form smaller, independently functioning units that are more akin to multiunit smooth muscle. In fact, electrical coupling of smooth-muscle units exhibits a tissue-specific continuum from multiunit to unitary coupling.
Action potentials of smooth muscles may be brief or prolonged
Although action potentials initiate contraction in both skeletal and cardiac muscle, diverse changes in membrane potential (Vm) can either initiate or modulate contraction in smooth-muscle cells. Action potentials that are similar to those seen in skeletal muscle are observed in unitary smooth muscle and in some multiunit muscles. Like cardiac muscle cells, some smooth-muscle cells exhibit prolonged action potentials that are characterized by a prominent plateau phase. Still other smooth-muscle cells cannot generate action potentials at all. In these cells, Vm changes in a graded fashion (see pp. 174–176) rather than in the all-or-none manner of action potentials. The stimuli that produce a graded response of Vm include many circulating and local humoral factors as well as mechanical stimuli such as stretching of the cell. These graded Vm changes may be either hyperpolarizing or depolarizing; they sum temporally as well as spatially. If the summation of graded depolarizations brings Vm above threshold, action potentials will fire in electrically excitable smooth-muscle cells.
Action potentials—characteristic responses of unitary (visceral) smooth muscle—typically have a slower upstroke and longer duration (up to ~100 ms) than do skeletal muscle action potentials (~2 ms). The action potential in a smooth-muscle cell can be a simple spike, a spike followed by a plateau, or a series of spikes on top of slow waves of Vm (Fig. 9-14A). In any case, the depolarizing phase of the action potential reflects opening of L-type voltage-gated Ca2+ channels. The initial inward Ca2+ current further depolarizes the cell and thereby causes still more voltage-gated Ca2+ channels to open in positive-feedback fashion. Thus, some smooth-muscle cells exhibit the same type of regenerative all-or-none depolarization that is seen in skeletal muscle. However, the rate of rise of the action potential in smooth muscle is typically slower because Cav channels (see pp. 190–193) open more slowly than do Nav channels (see pp. 187–189) of skeletal and cardiac muscle. Repolarization of the smooth-muscle cell is also relatively slow because L-type Cav Ca2+ channels exhibit prolonged openings and inactivate slowly. In addition, the slow repolarization reflects the delayed activation of voltage-gated K+ channels and, in many cases, Ca2+-activated K+channels, which depend on significant elevation of [Ca2+]i.
FIGURE 9-14 Action potentials and slow waves in smooth muscle.
Some smooth-muscle cells also express fast voltage-gated Na+ channels. However, these channels do not appear to be necessary for generating an action potential but rather contribute to a greater rate of depolarization and thus the activation of voltage-gated Ca2+ channels.
In some types of unitary smooth muscle, repolarization is so delayed that the action potential waveform displays a prominent plateau lasting several hundred milliseconds—as in cardiac muscle. Plateau action potentials occur in smooth muscle of the genitourinary tract, including the ureters, bladder, and uterus. The long plateau allows prolonged entry of Ca2+, thereby elevating [Ca2+]i and prolonging the contraction.
Some smooth-muscle cells spontaneously generate either pacemaker currents or slow waves
Although smooth-muscle cells undergo changes in Vm in response to neural, hormonal, or mechanical stimulation, many smooth-muscle cells are capable of initiating spontaneous electrical activity. In some tissues, this spontaneous activity results from pacemaker currents. In the intestine for example, special pacemaker cells called interstitial cells of Cajal initiate and control rhythmic contractions of the smooth-muscle layers. Pacemaker electrical activity arises from time- and voltage-dependent properties of ion channels that spontaneously produce either an increase in inward depolarizing currents (e.g., voltage-gated Ca2+ currents) or a decrease in outward hyperpolarizing currents (e.g., voltage-gated K+ currents). If Vm reaches threshold, an action potential fires.
In other smooth-muscle cells, this spontaneous electrical activity results in regular, repetitive oscillations in Vm—and contractions—that occur at a frequency of several cycles per minute. These are referred to as slow waves (see Fig. 9-14B). One hypothesis regarding the origin of slow-wave potentials suggests that voltage-gated Ca2+ channels—active at the resting Vm—depolarize the cell enough to activate more voltage-gated Ca2+ channels. This activation results in progressive depolarization and Ca2+ influx. The increase in [Ca2+]i activates Ca2+-dependent K+ channels, which leads to progressive hyperpolarization and eventual termination of the depolarization. These periodic depolarizations and [Ca2+]i increases cause periodic tonic contractions of the smooth muscle. When the amplitude of the slow Vm waves is sufficient to depolarize the cell to threshold, the ensuing action potentials lead to further Ca2+ influx and phasic contractions.
Oscillations in intracellular ions (other than Ca2+) or molecules may also explain spontaneous electrical activity. For example, increased [Ca2+]i during an action potential might stimulate Na-Ca exchange and lead to a cyclic increase in [Na+]i and thus an increase in the rate of Na+ extrusion by the electrogenic Na-K pump. Alternatively, activation of G protein–coupled receptors may lead to the formation of inositol 1,4,5-trisphosphate (IP3), thereby opening the IP3 receptor (IP3R) channel (see Table 6-2, family No. 18) and releasing Ca2+. The rise in [Ca2+]i would be self-reinforcing because CICR via RYRs (Fig. 9-15) may propagate through the cell as a Ca2+ wave. However, high [Ca2+]i levels inhibit RYR. The Ca2-release events ultimately terminate as high [Ca2+]i inhibits RYR, SR Ca2+ stores become depleted, or re-uptake of Ca2+into the SR occurs. The [Ca2+]i increases may themselves lead to periodic electrical activity by stimulating Ca2+-activated inward currents (e.g., Cl− efflux) and outward currents (e.g., K+ efflux; see below).
FIGURE 9-15 EC coupling in smooth muscle. PIP2, phosphatidylinositol 4,5-bisphosphate; PLA, phospholipase A; STIC, spontaneous transient inward current; STOC, spontaneous transient outward current.
Some smooth muscles contract without action potentials
Whereas generation of an action potential is essential for initiating contraction of skeletal and cardiac muscle, many smooth-muscle cells contract despite being unable to generate an action potential. As discussed above, Vm oscillations can lead to tonic contractions in the absence of action potentials. Action potentials usually do not occur in multiunit smooth muscle. For example, in the smooth muscle that regulates the iris of the eye, excitatory neurotransmitters such as norepinephrine and ACh cause a local depolarization—the junctional potential—which is similar to the end-plate potential in skeletal muscle (see p. 210). Junctional potentials spread electrotonically (i.e., in a graded fashion) throughout the muscle fiber, thereby altering Vm and triggering Ca2+ entry Ca2+ through L-type Cav channels. Graded changes in Vm may also modulate—by an unknown mechanism—the activity of the enzyme phospholipase C, which cleaves phosphoinositides to release the intracellular second messengers diacylglycerol (DAG) and IP3(see p. 58). Both second messengers are modulators of contractile force. In the absence of action potentials, some unitary smooth muscle, including some vascular smooth muscle, also contracts as a result of graded Vm changes.
Some smooth-muscle cells contract simply in response to extracellular agonists, with minimal depolarization and negligible Ca2+ entry from the outside. For example, a neurotransmitter can bind to a receptor, activate a G protein, and—via phospholipase C—lead to the generation of IP3, binding to IP3R, and Ca2+ release from the SR.
In smooth muscle, both entry of extracellular Ca2+ and intracellular Ca2+ spark activate contraction
Whereas striated muscle has T tubules, smooth muscle has more rudimentary and shallow invaginations of the plasma membrane (see Fig. 9-15) called caveolae (see pp. 42–43). Smooth-muscle cells use three major pathways—not mutually exclusive—for producing the rise in [Ca2+]i that triggers contraction (see Fig. 9-15): (1) Ca2+ entry through L-type Cav channels in response to depolarization, (2) Ca2+ release from the SR via RYR and IP3R Ca2+-release channels, and (3) Ca2+ entry through voltage-independent/store-operated channels.
Ca2+ Entry via Voltage-Gated Channels
Whether the smooth-muscle cell responds to graded depolarizations or action potentials, depolarization may produce a Ca2+ influx through L-type Cav channels.
Ca2+ Release from the SR
Sarcoplasmic Ca2+ release—seen as Ca2+ sparks (see pp. 242–243) if sufficiently robust—may occur by either of two mechanisms in smooth muscle: (1) Ca2+ entry through small clusters of the Cav1.2 variant of L-type channels, activating the RYR3 subtype of ryanodine receptors and causing CICR—a robust amplification of the Ca2+ signal; and (2) IP3 activation of IP3R. Ca2+ sparks in various smooth-muscle cells also may occur spontaneously due to random low-probability opening of RYR channels. Whereas the rise of [Ca2+]i via CICR is a prominent aspect of cardiac muscle, the receptor-mediated IP3 pathway is particularly significant for SR Ca2+ release in smooth muscle.
In smooth muscle, the relationship between the plasma membrane and the SR is not as regular as the triads (see p. 229) and dyads (see pp. 242–243) in striated muscle. At the level of the caveolae, a peripheral SR compartment encircles the invaginating plasma membrane—forming a gap of only 15 nm—facilitating Ca2+ diffusion and thus CICR. A larger network of central SR runs along the long axis of the cell, playing greater role in delivering Ca2+ to intracellular myofilaments for contraction.
In smooth muscle but not in cardiac muscle, the rise in [Ca2+]i stimulates Ca2+-activated ion channels other than RYR (e.g., Ca2+-activated K+ channels and Ca2+-activated Cl− channels) that participate in repolarization and regulation of contractile tone. N9-10
STOCs and STICs in Smooth Muscle
Contributed by Ed Moczydlowski
Simultaneous imaging of Ca2+ spark events and electrophysiological recording from smooth-muscle cells has further revealed that individual Ca2+-release spark events are often coupled to electrical signals at the plasma membrane known as STOCs (spontaneous transient outward currents) and STICs (spontaneous transient inward currents). STOCs and STICs are produced, respectively, by Ca2+-activated K+channels and by Ca2+-activated Cl− channels at the plasma membrane that are directly activated by the pulse of Ca2+ released from SR stores by spark events (see Fig. 9-15).
Ca2+-activated K+ channels in the smooth-muscle plasma membrane include BKCa channels activated both by [Ca2+]i and positive voltage as well as SK and IK channels activated by intracellular Ca2+-CaM. Close reciprocal coupling between intracellular Ca2+ release and activation of Ca2+-activated K+ channels, particularly BKCa channels, is recognized as an important negative-feedback mechanism for control of excitability, contraction, and smooth-muscle tone, a term that describes the underlying state of contractile tension. Membrane hyperpolarization mediated by opening of BKCa channels is a negative-feedback response that protects smooth muscle from excessive excitation and contraction.
In most smooth-muscle cells, the Nernst potential for Cl− (ECl) is on the order of −20 mV, which is significantly more positive than the typical smooth-muscle cell resting membrane potential of approximately −60 mV. In this situation, the Ca2+-activated opening of Cl− channels at membrane potentials more negative than ECl will depolarize the cell due to efflux of Cl− (which is equivalent to inward movement of positive charge and physiologically defined as an inward current). Ca2+-activated Cl− channels of the anoctamin family (see Table 6-2, family No. 17) have recently been identified in smooth muscle, epithelia, and other cells. Inward current due to Cl− efflux initiated by agonist-induced activation of IP3Rs resulting in a global increase in [Ca2+]i has been observed in many types of smooth-muscle cells. Since STIC responses depolarize Vm, they increase excitability and promote smooth-muscle contraction.
The ultimate consequences of changes in membrane potential, transmitter activation, and Ca2+ spark signaling in smooth muscle depend on complex interactions of ionic gradients and channels. For example, at very negative values of Vm, Ca2+ sparks can augment membrane depolarization by activation of Ca2+-activated Cl− current (STICs). The subsequent rise in Vm will subsequently activate L-type Cav channels to further enhance depolarization, Ca2+ entry, and muscle cell contraction. Eventually the opening of BKCa channels activated by positive voltage and the rise in [Ca2+]i will hyperpolarize the cell, inhibit further Ca2+ entry, and lead to muscle cell relaxation. Complex sequences of such events associated with Ca2+ sparks, Ca2+ waves, and Ca2+ oscillations underlie the tonic and phasic behavior of Ca2+signaling in smooth muscle.
Ca2+ Entry through Store-Operated Ca2+ Channels (SOCs)
In cells that lack Cav channels—including secretory epithelia, mast cells, and lymphocytes—depletion of Ca2+ from ER storage compartments may trigger Ca2+ influx through the plasma membrane, followed by the active uptake of this Ca2+ into the ER to replenish the Ca2+ store. This Ca2+-release–activated Ca2+ current (ICRAC) underlies capacitative Ca2+ entry, also known as store-operated Ca2+ entry (SOCE). Work on lymphocytes has identified three genes that encode the Orai family of SOCs (see Table 6-2, family No. 20 and Fig. 6-20X). N9-13 Missense mutations in the human ORAI1 gene eliminate the ICRAC vital for lymphocyte activation, resulting in severe combined immunodeficiency syndrome (SCID).
Store-Operated Ca2+ Channels (SOCs)
Contributed by Emile Boulpaep, Walter Boron
Receptor-operated and store-operated Ca2+ channels are defined not by the structure of the channel but by their apparent physiological regulation.
Receptor-operated Ca2+ channels (ROCs)—also called “second messenger-operated channels”—mediate Ca2+ entry in response to stimulation of a Gq protein-coupled receptor (see Table 3-2) or a receptor tyrosine kinase (see p. 68) and subsequent increase in the activity of phospholipase C (see p. 58), such as PLCβ or PLCγ.
Store-operated Ca2+ channels (SOCs) mediate “capacitative” Ca2+ entry that is triggered by depletion of Ca2+ inside the endoplasmic reticulum. Thapsigargin, a specific inhibitor of the endoplasmic reticulum Ca2+ pump or SERCA, can cause depletion of the internal Ca2+ pool. As discussed on p. 247, one class of SOCs consists of the ORAI channels and their associated STIM proteins.
Although the ORAI channel and STIM proteins comprise a pathway for voltage-independent activation of SOC in smooth muscle, recent evidence suggests that the Ca2+-permeable TRP channels (see Fig. 6-20I as well as p. 169)—TRPC1 and TRPC5—may function as SOCs in mammalian portal-vein myocytes. Activation of these latter TRP channels in portal-vein smooth muscle appears to be coupled to IP3-mediated release of internal Ca2+ via mechanisms involving α1-adrenergic receptor activation of a phospholipase C pathway that includes IP3, diacylglycerol, protein kinase C, and calmodulin. Further work is clearly needed to investigate the molecular basis of SOC channels in smooth muscle and the physiological functions of human ORAI channels.
Yildirim E, Kawasaki BT, Birnbaumer L. Molecular cloning of TRPC3a, an N-terminally extended, store-operated variant of the human C3 transient receptor potential channel. Proc Natl Acad Sci USA. 2005;102:3307–3311.
Albert AP, Saleh SN, Peppiatt-Wildman CM, Large WA. Multiple activation mechanisms of store-operated TRP channels in smooth muscle cells. J Physiol. 2007;583(1):25–36.
In nonexcitable cells, the Orai channel is under the control of the Ca2+-sensing STIM protein in ER membrane (see Fig. 9-15). When ER [Ca2+] is depleted, Ca2+ dissociates from a binding site on the N terminus of STIM, which causes STIM to aggregate in regions of the ER membrane that are closely associated with the plasma membrane. This STIM aggregation then triggers a direct interaction of the cytosolic C terminus of STIM with a coiled-coil domain on the cytosolic C terminus of Orai tetramers. The result is a clustering of Orai tetramers to form active Ca2+ channels that mediate Ca2+ influx across the plasma membrane and subsequent refilling of the ER stores. As ER [Ca2+] rises, Ca2+ again binds to the site on STIM, suppressing STIM aggregation, and halting SOCE.
SOCE is clearly involved in the Ca2+-dependent regulation of smooth-muscle contraction. Many types of smooth muscle express STIM and Orai proteins. Ca2+-permeable channels of the TRP family (see Table 6-2) are also present in smooth muscle and may be involved in SOCE. N9-11
SOCE in Skeletal Muscle
Contributed by Ed Moczydlowski
The possible role of SOCE in the physiology of other muscle cell types is also under active investigation. For example, skeletal muscle fibers express both the STIM and Orai proteins. Human mutations in the human ORAI1 gene are associated with congenital myopathy, but the exact function of the gene product in muscle is unclear. Hypothetical proposed roles for plasma membrane entry of Ca2+ by the SOCE mechanism in skeletal muscle include supplementation of intracellular Ca2+ for activation of contraction, balancing of Ca2+ influx and depletion, and regulation of protein function at the triad junction.
Both Ca2+ release from the SR and the entry of Ca2+ via SOCE are voltage independent. These two mechanisms underlie pharmacomechanical coupling, a form of EC coupling in which intracellular release of Ca2+ is initiated by chemical activators rather than membrane voltage changes. Thus, a variety of drugs, excitatory neurotransmitters, and hormones can induce smooth-muscle contraction by these coupling mechanisms independently of action potential generation, as discussed in the previous section, and also independently of direct changes in [Ca2+]i, as discussed below.
Ca2+-dependent phosphorylation of the myosin regulatory light chain activates cross-bridge cycling in smooth muscle
As we noted above, because smooth-muscle actin and myosin are not as highly organized as in skeletal and cardiac muscle, smooth muscle does not exhibit striations characteristic of skeletal and cardiac muscle. The actin filaments of smooth muscle are oriented mainly parallel or oblique to the long axis of the cell. Multiple actin filaments are joined at specialized locations in the cell called dense bodies, which contain α-actinin and are analogous to the filament-organizing Z lines of striated muscle. Dense bodies are found immediately beneath the cell membrane as well as within the interior of the myocyte. Thick filaments are interspersed among the thin filaments in smooth muscle and are far less abundant than in skeletal or cardiac muscle.
In contrast to the mechanism in striated muscle, an entirely different mechanism controls cross-bridge turnover in smooth muscle, where an increase in [Ca2+]i initiates a slow sequence of biochemical events that ultimately increases the ATPase activity of the myosin (Fig. 9-16). The first step is the binding of four Ca2+ ions to calmodulin (CaM), which is closely related to troponin C of striated muscle (see p. 233). Next, the Ca2+-CaM complex activates an enzyme known as myosin light chain kinase (MLCK), which in turn phosphorylates the regulatory light chain that is associated with each neck of the dimeric myosin II heavy chain (see pp. 233–234). Phosphorylation of the light chain causes a conformational change of the myosin head, which increases the angle between the head and neck domain of myosin and also increases its ATPase activity, allowing it to interact efficiently with actin and act as a molecular motor. Thus, in smooth muscle, CaM rather than troponin C is the Ca2+-binding protein responsible for transducing the contraction-triggering increases in [Ca2+]i. Note that in smooth muscle, contraction cannot begin until MLCK increases the ATPase activity of myosin, which is a relatively slow, time-dependent process. In skeletal and cardiac muscle, on the other hand, the ATPase activity of the myosin head is constitutively high, and cross-bridge cycling begins as soon as tropomyosin moves out of the way.
FIGURE 9-16 Role of Ca2+ in triggering the contraction of smooth muscle.
In addition to activating thick filaments of smooth muscle, Ca2+-CaM indirectly acts on the thin filaments to remove the tonic inhibition to actin-myosin interactions that are caused by steric hindrance. Two proteins, caldesmon and calponin, tonically inhibit the interaction between actin and myosin. Both are Ca2+-CaM–binding proteins, and both bind to actin and tropomyosin. Calponin, which is found in a fixed stoichiometry with tropomyosin and actin (one calponin–one tropomyosin–seven actin monomers), tonically inhibits the ATPase activity of myosin. The Ca2+-CaM complex not only activates MLCK (a CaMK; see p. 60) but also has two effects on calponin. First, Ca2+-CaM binds to calponin. Second, Ca2+-CaM activates CaMKII, which phosphorylates calponin. Both effects relieve calponin's inhibition of myosin's ATPase activity. Caldesmon is another regulatory protein of smooth muscle that appears to act like calponin by tonically inhibiting the actin-activated ATPase activity of myosin in smooth muscle. Caldesmon contains binding domains for actin, myosin, and tropomyosin, as well as Ca2+-CaM. It appears to block the interaction of actin with myosin; however, the exact mechanism is controversial.
Although the steps of cross-bridge cycling in smooth muscle are similar to those in skeletal and cardiac muscle (see Fig. 9-7), smooth muscle controls the initiation of the cross-bridge cycle differently—at step 2 in Figure 9-7, where Ca2+ confers ATPase activity to the myosin head, as discussed before. Recall that the ATPase activity of striated muscle is always high and Ca2+ regulates the access of the myosin head to the actin. Another difference between smooth and striated muscle is that the frequency of cross-bridge cycling in smooth muscle is less than one tenth that in skeletal muscle. This variation reflects differences in the properties of myosin isoforms that are expressed in various cell types. Even though cross-bridge cycling occurs less frequently in smooth muscle, force generation may be as great or greater, perhaps because the cross-bridges remain intact for a longer period with each cycle. It is likely that this longer period during which the cross-bridges are intact reflects a lower rate of ADP release from the smooth-muscle isoform of myosin.
Termination of smooth-muscle contraction requires dephosphorylation of myosin light chain
Because Ca2+ triggers smooth-muscle contraction by inducing phosphorylation of the myosin regulatory light chain rather than by simple binding to troponin C as in striated muscle, merely restoring [Ca2+]i to its low resting value does not produce muscle relaxation. Rather, relaxation of smooth muscle requires dephosphorylation of the myosin light chains (MLCs) by myosin light chain phosphatase (MLCP). This phosphatase is a heterotrimer consisting of subunits with molecular masses of 130, 20, and 37 kDa. The 130-kDa subunit confers specificity by binding to myosin; the 37-kDa protein is the catalytic subunit responsible for the dephosphorylating activity.
Smooth-muscle contraction may also occur independently of increases in [Ca2+]i
Whereas many excitatory stimuli rely on increases in [Ca2+]i to evoke contraction, some stimuli appear to cause contraction without a measurable increase in [Ca2+]i. One mechanism by which excitatory stimuli might induce Ca2+-independent contractions is by modulating the activity of contractile or regulatory proteins directly. Thus, the amount of force developed at any given [Ca2+]i may vary. This force/[Ca2+]i ratio may be increased or decreased and is generally higher during pharmacomechanical activation than during depolarization-activated contractions. Because phosphorylation of the MLC is a major determinant of contractile force in smooth muscle, Ca2+-independent contractions may result either from an increase in the rate of MLC phosphorylation by MLCK or from a decrease in the rate of MLC dephosphorylation by MLCP. One second-messenger system that can decrease the activity of phosphatases is protein kinase C (PKC; see pp. 60–61). Some excitatory stimuli are therefore capable of initiating smooth-muscle contraction by inducing IP3-mediated release of Ca2+ from intracellular stores as well as by producing PKC-mediated decreases in MLCP activity. These pathways are further examples of pharmacomechanical coupling (see p. 247).
In smooth muscle, increases in both [Ca2+]i and the Ca2+ sensitivity of the contractile apparatus enhance contractile force
Unlike skeletal muscle, in which force development results from the summation of individual muscle twitches, individual smooth-muscle cells can maintain a sustained contraction that can be graded in strength over a wide range. Contractile force in smooth muscle largely depends on the relative balance between the phosphorylation and dephosphorylation of MLCs. The rate of MLC phosphorylation is regulated by the Ca2+-CaM complex, which in turn depends on levels of intracellular Ca2+. Smooth-muscle cells can regulate [Ca2+]i over a wider range than skeletal and cardiac muscle for several reasons. First, smooth-muscle cells that do not generate action potentials—but rather exhibit graded Vm responses to neurotransmitters or hormones—are able to fine-tune Ca2+ influx via voltage-gated channels. Second, release of Ca2+ from intracellular stores may be modulated via neurotransmitter-induced generation of intracellular second messengers such as IP3. This modulation allows finer control of Ca2+ release than occurs in the SR Ca2+-release channel by L-type Ca2+ channels in skeletal and cardiac muscle.
A second level of control over contractile force occurs by regulation of the Ca2+sensitivity of proteins that regulate contraction. For example, inhibiting MLCP alters the balance between phosphorylation and dephosphorylation, in effect allowing a greater contraction at a lower [Ca2+]i. Some neurotransmitters act by inhibiting the phosphatase, which appears to occur via activation of G protein–coupled receptors. Another mechanism for governing the Ca2+ sensitivity of proteins that regulate contraction is alteration of the Ca2+ sensitivity of the MLCK. Phosphorylation of MLCK by several protein kinases—including PKA, PKC, and CaMK—decreases the sensitivity of MLCK to activation by the Ca2+-CaM complex.
Smooth muscle maintains high force at low energy consumption
Smooth muscle is often called on to maintain high force for long periods. If smooth muscle consumed ATP at rates similar to those in striated muscle, metabolic demands would be considerable and the muscle would be prone to fatigue. Unlike striated muscle, however, smooth muscle is able to maintain high force at a low rate of ATP hydrolysis. This low energy consumption/high-tension state is referred to as the latch state. The latch state in smooth muscle is unique because high tension can be maintained despite a decrease in the degree of muscle activation by excitatory stimuli. As a result, force is maintained at a lower level of MLCK phosphorylation.
The mechanism underlying the latch state is not entirely known, although it appears to be due in large part to changes in the kinetics of actin-myosin cross-bridge formation and detachment. These changes may be a direct result of a decrease in the rate at which dephosphorylated cross-bridges detach. Tension is directly related to the number of attached cross-bridges. Furthermore, the proportion of myosin heads cross-bridged to actin is related to the ratio of attachment rates to detachment rates. Therefore, it is reasonable to expect that a decrease in the detachment rate would allow a greater number of cross-bridges to be maintained and would result in a lower rate of cross-bridge cycling and ATP hydrolysis. Thus, smooth muscle appears to be able to slow down cross-bridge cycling just before detachment, a feat that can be accomplished in skeletal muscle (see Fig. 9-7) only at low ATP levels (as in rigor mortis).