Smooth Muscle

"Discuss the mechanisms regulating contraction of smooth muscle."

Smooth muscle forms the walls of the viscera, blood vessels, passages in the airway, etc. It is so named because under the electron microscope it does not show the striations that appear in skeletal and cardiac muscle. This is because the arrangement of the contractile protein filaments is not in strict transverse alignment as in the other two types of muscle. The filaments are instead attached to certain ‘dense bodies’ throughout the cytoplasm. Where these occur near the cell membrane connections are made between the dense bodies of adjoining cells. This enables the smooth muscle to maintain its structural integrity under stress.

Contraction of smooth muscle is by sliding of adjacent filaments. The contraction itself is thought to be the result of the binding of components on the thick myosin filaments (‘the heads’), with various sites on the thin actin filaments, to form a crossbridge.

There are thought to be two alternative cycles for the contractile mechanism. One is involved in fast twitch-type contraction and the other in the more prolonged tonic contractions. The fast cycle involves continued phosphorylation of the cross-bridge and is in two stages.

The ATPase in the myosin heads is activated by phosphorylation and attaches the head to actin binding sites. In the process of binding it straightens out and slides the actin filament past the myosin, hydrolysing one ATP molecule in the process. The cross bridge then rapidly detaches.

The second, slower mechanism involves phosphorylation of the mysosin head, attachment and straightening at the actin site, de-phosphorylation and detachment. The dephosphorylation leads to a longer time before the cross bridge detaches. Using this second system is less efficient in terms of ATP used as this cycle uses 2 ATP molecules; one in the movement of the filaments and one in its’ regulation. The efficiency of smooth muscle (mechanical energy/ATP hydrolysed) is estimated at between 15% and 20% compared to 40% of skeletal muscle. However, in continued, tonic contraction the slower rate of detachment of the crossbridges means that the overall efficiency of the muscle fibre is much increased. In these conditions, where the efficiency is zero (no actual work is being done), the increased time taken for the cross bridges to detach allows smooth muscle to maintain it’s force of contraction far better than skeletal muscle. This can use up to 300 times less ATP than a skeletal muscle fibre doing the same job.

In smooth muscle, contraction is initiated by the increase of calcium within the cell. Supplies of calcium for the myoplasm come from two sources; the extra cellular Ca²⁺ and the stores in the sarcoplasmic reticulum. Release of some calcium from the sarcoplasmic reticulum is initiated by the binding of IP₃ to receptors on its membrane opening Ca²⁺ channels.

The IP₃ comes to the sarcoplasmic reticulum via a complex pathway that allows strict regulation of calcium release. The initial stimulus acts on receptors in the sarcolemma that release a guanine nucleotide binding protein (G-protein) to activate phospholipase C. Phospholipase C then hydrolyses phosphatidyl bisphosphate to release IP₃.

Further channels are controlled by the amount of calcium already in the cells. These are known as ryanodine receptors due to the ability of the plant alkaloid ryanodine to lock them open. They open as the concentration of Ca²⁺ increases and are responsible for the generating of spontaneous action potential within some types of smooth muscle.

The sarcolemma also operates to control the amount of calcium ions in the cell. For removing excess calcium there are active transport mechanisms that pump calcium directly out of the cell and there is a Ca²⁺-Na⁺ exchanger that allows in three sodium ions in exchange for each calcium ion.

Reclaiming of calcium for the sarcoplasmic reticulum is not yet clear but the process is dependent on the level of extracellular Ca²⁺.

Influx of calcium is controlled by two classes of channel protein; receptor-activated channels and potential dependent channels. Smooth muscle shows the rare ability to have contractions induced by neurotransmitters or hormones with very little change in membrane potential. This is pharmaco-mechanical coupling. Such channels can also be linked by G-proteins to inhibitory neurotransmitters and hormones.

Contained in the sarcolemma are also voltage-dependent Ca²⁺ channels whose summed conductance increases with depolarisation. This means that some control of calcium concentration is by control of the cell's membrane potential. Some of this can be by depolarisation of membrane from action potentials or by propagation of depolarisation from adjacent cells, via gap junctions. The presence of an electrogenic potassium-sodium pump also adds to the polarisation of the cell membrane and as such can be mediated to control intracellular calcium.

This intracellular calcium regulates contraction. The enzyme which the calcium is thought to control is myosin kinase. It does this by binding to a second protein, calmodulin, which then complexes with, and activates, myosin kinase.

In the relaxed state there is a low myoplasmic concentration of calcium ions, no myosin kinase is activated and no cycling of cross-bridges occurs. If the muscle is then stimulated, the myoplasmic calcium levels rise considerably and myosin kinase is activated. Then causes rapid phosphorylation of all the myosin heads, and the fast cross-bridge cycle is initiated. If the myoplasmic calcium falls to moderate levels, as it will tend to do with a continued stimulus, then fewer of the myosin heads will remain phosphorylated at the fourth stage of the cycle. There will then be a delay before the cross-bridge separates. The muscle will be using the slower contraction cycle.

Control of some smooth muscle contraction is achieved by controlling the levels of cyclic AMP in the cell. In high concentrations this acts to inhibit activity of the myosin kinase. As such it relaxes smooth muscle. This occurs noticeably in vascular smooth muscle.

External control of smooth muscle is by a number of means. Much control is by innervation of the muscle. The origin of these nerves may be extrinsic from the autonomic nervous system, intrinsic from plexuses within the smooth muscle tissue or afferent sensory neurons that mediate various reflexes.

Each terminal branch of the autonomic system passes close to the cell and has a series of swollen areas or varicosities spread along the axon. Each of these varicosities contains the neurotransmitter and is equivalent to the more complex neuromuscular junction found in innervation of skeletal muscle. In the spontaneous muscle of the gut innervation may, instead, be by axon muscles. These end near to a patch of muscle rather than innervating each muscle cell individually. It is the gap junctions between the cells that make this possible.

The many differences in response between tissues are dictated by the differences in innervation, type of transmitter released and nature of receptors for each transmitter. Release of adrenaline or noradrenaline from nerve endings causes hyperpolarization of the membrane and a decrease in the frequency of the waves of depolarisation. Cholinergic nerve endings have the opposite effect.

Contractile responses may also be modulated by the surrounding cells rather than by innervation. An example often cited is the relationship between the smooth muscle surrounding the arteries and the endothelium which lies on the lumenal side of this muscle. Acetylcholine is known to act on endothelial receptors and to relax smooth arterial muscle. Nitric Oxide in this case has been identified as the chemical released from the endothelium to produce relaxation of the muscle.

Another example is that in increased metabolic activity of skeletal muscle adenosine is produced. Receptors on the smooth muscle cells of the arteries cause the muscle to relax and induces vasodilatation. Result? Increase in blood supply to the muscle during periods of high activity.

Smooth muscle is also regulated by circulating hormones and receptors for adrenaline are common on the sarcolemma.

Smooth muscle cells are also able to show spontaneous activity. The membrane potential rises and falls in slow waves. It is not known precisely how this happens but two methods are proposed. The sodium pump is thought either to have a rhythmic pattern of activity, or the ion conductances across the membrane are constantly changing. Every now and again the membrane potential reaches threshold level (~35mV) and initiates an all or nothing action potential. Stretching of the muscle cell depolarises the fibre and thus increases the frequency of action potentials. This can account for the contraction of smooth muscle when resisting external extension. However there is no spontaneous activity in smooth muscle of the iris, nictitaing membrane and vas deferens which are under semi-voluntary control. The action potentials have shown themselves to be insensitive to tetrodotoxin or lack of sodium in the extracellular fluid. However, addition of calcium channel blockers such as manganese, lanthanum, cobalt and the drugs verapamil and nifedipine will prevent action potential firing. Calcium can be shown to be the major controlling ion in smooth muscle cells.