Excitation-contraction coupling

Excitation-contraction (EC) coupling is a term coined in 1952 to describe the physiological process of converting an electrical stimulus to mechanical response. 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. Acetylcholine is released by the motor neuron into the neuromuscular junction via exocytosis of synaptic vesicles in response to an action potential generated by the motor cortex.

2. An action potential is generated in across the membrance of the myocyte in response to binding of acetylcholine to ligand-gated sodium channels and is propagated across the surface membrane and down T tubules of the muscle cell.

3. The action potential in the T tubules activate the voltage-sensing dihydropyridine receptor

4. Triadic feet which span the cytoplasmic gap between the T-tubule and the sarcoplasmic reticulum transmit the voltage-mediated signal to ryanodine receptors, removing their intracellular domain from obstructing the pore of the channel.

5. Ryanodine receptors act as calcium release channels, and calcium is released from the sarcoplasmic reticulum into the cytoplasm.

6. Calcium ions released from lateral sacs bind to Troponin C on actin filaments, which subsequently leads to tropomyosin being physically moved aside to uncover cross-bridge binding sites on the actin filament.

7. Myosin forms a cross bridge onto the actin filaments active site, and pull the actin toward the center of the sarcomere. This process is powered by energy provided by ATP hydrolysis.

8. Ca2+ is actively taken up by the sarcoplasmic reticulum when there is no longer a local action potential present.

9. With Ca2+ no longer bound to troponin, tropomyosin slips back to its blocking position over the binding sites on actin. Contraction ends and actin slides back to original resting position.

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 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 triggers L-type calcium channels during the plateau phase 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 tropomyosin 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 plasma membrance Calcium ATPase.

7. Intracellular calcium concentration drops and tropomyosin complex returns over the active site of the actin filament, ending contraction.