Excitation-contraction coupling

Excitation-contraction (EC) coupling is a term coined in 1952 to describe the physiological process of converting an electrical stimulus to a mechanical response ^[1]. This process is fundamental to muscle physiology, whereby the electrical stimulus is usually an action potential and the mechanical response is contraction. EC coupling can be dysregulated in many disease conditions.

Though EC coupling has been known for over half a century, it is still an active area of biomedical research. The general scheme is that an action potential arrives to depolarize the cell membrane. By mechanisms specific to the muscle type, this depolarization results in an increase in cytosolic calcium that is called a calcium transient. This increase in calcium activates calcium-sensitive contractile proteins that then use ATP to cause cell shortening.

Skeletal muscle

In skeletal muscle the method of excitation contraction coupling relies on the ryanodine receptor being activated by a domain spanning the space between the T tubules and the sarcoplasmic reticulum to produce the calcium transient responsible for allowing contraction.

1. The alpha motor neuron produces an action potential that propagates down its axon to the neuromuscular junction.
2. The action potential is sensed by a voltage-dependent calcium channel which causes an influx of Ca²⁺ ions. This influx results in exocytosis of synaptic vesicles containing acetylcholine.
3. Acetylcholine diffuses across the synapse and binds to nicotinic acetylcholine receptors on the myocyte, opening them. An influx of Na⁺ and an efflux of K⁺ results, depolarizing the cell and generating an end-plate potential.
4. The end-plate potential propagates throughout the myocyte's sarcolemma and into the T-tubule system.
5. The T-tubule system contains voltage-dependent calcium channels known as dihydropyridine receptors (DHP) which are activated by the end-plate potential.
6. Rather than releasing calcium from the T-tubules, activated dihydropyridine receptors transmit the voltage-mediated signal through a mechanical linkage to the ryanodine receptors in the sarcoplasmic reticulum. This process involves a conformational change which allosterically activates type 1 ryanodine receptors.
7. Activated ryanodine receptors then open their channels.
8. Opening of the ryanodine receptors allows a flow of Ca²⁺ from the sarcoplasmic reticulum into the cytoplasm. In this release, Ca²⁺ unbinds from the calcium-binding protein called calsequestrin.
9. Ca²⁺ released from the sarcoplasmic reticulum binds to Troponin C by the actin filaments, which subsequently causes the troponin complex to pull tropomyosin away from the myosin binding sites on nearby actin filaments. Myosin cross-bridge binding sites on the actin filaments are now uncovered.
10. By hydrolyzing ATP, myosin forms cross bridges with the actin filaments. Activation of this cross-bridge cycling may induce a shortening of the sarcomeres and the muscle as a whole, but not if the tension is insufficient to overcome the load imparted on the muscle.
11. Provided a force is applied that exceedes the load, a concentric contraction initiates. During this contraction, actin's interaction with myosin results in its movement toward the center of the sarcomere, or M-line, through a series of calcium-induced power strokes.
12. A sarcomere will remain contracted in this tightly bound state of rigor mortis unless sufficient ATP is present to bind with myosin, as a myosin head that is not bound to actin is bound to ATP.
13. Simultaneously, the sarco/endoplasmic reticulum Ca²⁺-ATPase actively pumps Ca²⁺ back into the sarcoplasmic reticulum where Ca²⁺ rebinds to calsequestrin.
14. With Ca²⁺ no longer bound to troponin C, the troponin complex slips position from the open state to its blocking position. As a consequence of this change, tropomyosin slips into a position that covers the binding sites on actin.
15. Since cross-bridge cycling is ceasing then any load on the muscle causes the inactive sarcomeres to lengthen.

Cardiac muscle

In cardiac muscle, the method is dependent on a phenomenon called calcium-induced calcium release, which involves the conduction of calcium ions into the cell triggering further release of ions into the cytoplasm (about 75% of calcium present in the cytoplasm during contraction is release from the sarcoplasmic reticulum).

1. An action potential is induced by pacemaker (conduction pathway) cells in the Sinoatrial node or Atrioventricular node and conducted from non-contractile cardiac myocytes to contractile cells through gap junctions.
2. The action potential travels along T-tubules among Z-discs and triggers L-type calcium channels (DHP) during the plateau phase of the cardiac action potential, causing a net flux of calcium ions into the cardiac myocyte.
3. The increase in intracellular calcium ions is detected by ryanodine receptors in the membrane of the sarcoplasmic reticulum which transport calcium out into the cytosol in a positive feedback physiological response.
4. The cytoplasmic calcium binds to Troponin C, moving the troponin complex off the actin binding site allowing the myosin head to bind to the actin filament.
5. Using ATP hydrolysis the myosin head pulls the actin filament to the centre of the sarcomere.
6. Intracellular calcium is taken up by the sarco/endoplasmic reticulum ATPase pump into the sarcoplasm, or ejected from the cell by the sodium-calcium exchanger or the plasma membrane calcium ATPase.
7. Intracellular calcium concentration drops and troponin complex returns over the active site of the actin filament, ending contraction.

Smooth muscle

Further information: Smooth muscle

It is important to note that contraction of smooth muscle need not require neural input--that is, it can function without an action potential. It does so by integrating a huge number of other stimuli such as humoral/paracrine (e.g. Epinephrine, Angiotensin II, AVP, Endothelin), metabolic (e.g. oxygen, carbon dioxide, adenosine, potassium ions, hydrogen ions), or physical stimuli (e.g. stretch receptors, shear stress). This integrative character of smooth muscle allows it to function in the tissues in which it exists, such as being the controller of local blood flow to tissues undergoing metabolic changes. In these excitation-free contractions, then, there of course is no excitation-contraction coupling.

Some stimuli for smooth muscle contraction, however, are neural. All neural input is autonomic (involuntary). In these the mechanism of excitation-contraction coupling is as follows: parasympathetic input uses the neurotransmitter acetylcholine. Acetylcholine receptors on smooth muscle are of the muscarinic receptor type; as such they are metabotropic, or G-protein / second messenger coupled. Sympathetic input uses different neurotransmitters; the primary one is norepinephrine. All adrenergic receptors are also metabotropic. The exact effects on the smooth muscle depend on the specific characteristics of the receptor activated--both parasympathetic input and sympathetic input can be either excitatory (contractile) or inhibitory (relaxing). The main mechanism for actual coupling involves varying the calcium-sensitivity of specific cellular machinery. However it occurs, increased intracellular calcium binds calmodulin, which activates myosin light chain kinase (MLCK). MLCK phosphorylates the regulatory light chains of the myosin heads. Phosphorylated myosin heads are able to cross bridge-cycle. Thus, the degree to and velocity of which a whole smooth muscle contracts depends on the level of phosphorylation of myosin heads. Myosin light chain phosphatase removes the phosphate groups from the myosin heads, thus ending cycling (and leaving the muscle in latch-state).

References

1. ^ Sandow A (1952). "Excitation-Contraction Coupling in Muscular Response". Yale J Biol Med 25 (3): 176–201. PMC 2599245. PMID 13015950. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2599245.