Question

List and briefly describe the mechanisms for smooth muscle contraction in terms of altering (increasing) the force of contraction.

Answer 1

Mechanism

Smooth muscle contraction is dependent on calcium influx. Calcium is increased within the smooth muscle cell through two different processes. First, depolarization, hormones, or neurotransmitters cause calcium to enter the cell through L-type channels located in the caveolae of the membrane. Intracellular calcium then stimulates the release of calcium from the sarcoplasmic reticulum (SR) by way of ryanodine receptors and IP3; this process is referred to as calcium-induced calcium release.Unlike skeletal muscle, smooth muscle calcium release from the sarcoplasmic reticulum is not physically coupled to the ryanodine receptor. Once calcium has entered the cell it is free to bind calmodulin, which transforms into activated calmodulin. Calmodulin then activates the enzyme myosin light chain kinase (MLCK), MLCK then phosphorylates a regulatory light chain on myosin. Once phosphorylation has occurred, a conformational change takes place in the myosin head; this increases myosin ATPase activity which promotes interaction between the myosin head and actin. Cross-bridge cycling then occurs, and tension is generated. The tension generated is relative to the amount of calcium concentration within the cell. ATPase activity is much lower in smooth muscle than it is in skeletal muscle. This factor leads to the much slower cycling speed of smooth muscle. However, the longer period of contraction leads to a potentially greater force of contraction in smooth muscle. Smooth muscle contraction is enhanced even further through the use of connexins. Connexins allow for intercellular communication by allowing calcium and other molecules to flow to neighboring smooth muscle cells. This action allows for rapid communication between cells and a smooth contraction pattern.

Steps involved in smooth muscle cell contraction:

1. Depolarization of membrane or hormone/neurotransmitter activation

2. L-type voltage-gated calcium channels open

3. Calcium-induced calcium release from the SR

4. Increased intracellular calcium

5. Calmodulin binds calcium

6. Myosin light chain kinase activation

7. Phosphorylation of myosin light chain

8. Increase myosin ATPase activity

9. Myosin-P binds actin

10. Cross-bridge cycling leads to muscle tone

Dephosphorylation of myosin light chains terminates smooth muscle contraction. Unlike skeletal muscle, smooth muscle is phosphorylated during its activation. This creates a potential difficulty in that simply reducing calcium levels will not produce muscle relaxation. Myosin light chain phosphatase (MLCP), instead, is responsible for dephosphorylation of the myosin light chains, ultimately leading to smooth muscle relaxation.

Another important clinical aspect of smooth muscle relaxation is the mechanism of nitric oxide. Nitric oxide is formed via nitric oxide synthase in endothelial cells; it is then able to diffuse out of the endothelium into smooth muscle cells. Nitric oxide then induces the conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP) by binding to and activating the enzyme guanylyl cyclase. In smooth muscle cells, the increase in cGMP will lead to stimulation of cGMP-dependent protein kinase which in turn activates MLCP, leading to dephosphorylation of myosin light chains and eventual smooth muscle relaxation.

Smooth muscle action potentials are unique in that membrane potential acts to initiate or modulate contraction. As such graded membrane response can be stimulated by multiple factors including local humoral factors, circulating hormones, or mechanical stimulation like stretching of the cells. Action potentials in smooth muscle cells are slower than skeletal action potentials, and they can last almost fifty times as long. This is thought to occur because calcium channels in smooth muscle cells open slower than skeletal muscle. This, in turn, leads to slow repolarization of smooth muscle as potassium channels are also slow to react. Sodium channels may also be present on the smooth muscle membrane and function by increasing the rate of depolarization and thus can aid in the activation of calcium channels.

Some smooth muscle cells also display the ability to form a spontaneous pacemaker current. This pacemaker current, for example, is maintained in the intestines by the interstitial cells of Cajal. The pacemaker current represents repetitive oscillations in the membrane potential that occur in several cycles. These slow waves of membrane potential fluctuation are unique in that they are not responsible for contraction of the intestines. It is thought that at resting membrane potential some voltage-gated calcium channels become active, an influx of calcium will then propagate a slow wave at a specific threshold. If the amplitude of the slow wave is high enough, L-type calcium channels will open, leading to contraction. Sodium may also play a role in the oscillating electrical activity. Calcium influx stimulates Na-Ca exchange which leads to an influx of sodium; this will effectively increase the rate of the Na-K pump. This all remains unique because the oscillations of the membrane potential and slow wave activity are generated without the influence of the central nervous system. The slow waves are therefore able to allow the smooth muscle to remain tonic without having to maintain continuous action potential firings.

Smooth muscle has also been observed to contract without any action potential. In multi-unit smooth muscle, action potentials usually do not occur. An example would be the smooth muscle in the iris of the eye where norepinephrine and ACh generate a depolarization that is called a junctional potential. In these situations, the neurotransmitters themselves generate the changes in the smooth muscle to cause the contraction. The junctional potential eventually triggers an influx of calcium through L-type channels. In some situations, the neurotransmitters may activate a G-protein which activates phospholipase C generating IP3; IP3 is then able to trigger calcium release from the sarcoplasmic reticulum.

Smooth muscle contractions may be required to last for a long time. The metabolic demand of sustained contraction would be far too costly if smooth muscle contractions occurred similarly to skeletal muscle. The muscle would most likely fatigue as intracellular supplies of ATP depleted. The mechanism that allows the smooth muscle to maintain high-tension at low energy consumption is termed the latch state. Even as levels of phosphorylated myosin light chain kinase decrease, smooth muscle tone will remain high.