Excitation–contraction coupling

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Excitation–contraction (E-C) 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. E-C coupling can be dysregulated in many diseases.Though E-C 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[edit]

In skeletal muscle, E-C coupling relies on a direct coupling between key proteins, the sarcoplasmic reticulum (SR) calcium release channel (identified as the ryanodine receptor, RyR) and voltage-gated L-type calcium channels (identified as dihydropyridine receptors, DHPRs). DHPRs are located on the sarcolemma (which includes the surface sarcolemma and the transverse tubules), while the RyRs reside across the SR membrane. The close apposition of a transverse tubule and two SR regions containing RyRs is described as a triad and is predominantly where E-C coupling takes place. E-C coupling proceeds as follows:

  1. The membrane potential of a skeletal muscle cell is depolarised by an action potential (e.g. from synaptic activation from an alpha motor neuron)
  2. This depolarisation activates voltage-gated DHPRs
  3. This activates RyR type 1 via physical linkage (involving conformational changes that allosterically activates the RyRs)
  4. As the RyRs open, calcium is released from the SR into the local junctional space, which then diffuses into the bulk cytoplasm to cause a calcium transient. Note that the SR has a large calcium buffering capacity partially due to a calcium-binding protein called calsequestrin
  5. The calcium released into the cytosol binds to Troponin C by the actin filaments, to allow cross-bridge cycling, producing force and, in some situations, motion
  6. The sarco/endoplasmic reticulum calcium-ATPase (SERCA) actively pumps calcium back into the SR
  7. As calcium declines back to resting levels, the force declines and relaxation occurs

Cardiac muscle[edit]

Unlike skeletal muscle, E-C coupling in cardiac muscle is thought to depend primarily on a mechanism called calcium-induced calcium release.[2] Though the proteins involved are similar, the DHPR and RyR (type 2) are not physically coupled. Instead, RyRs are activated by a calcium trigger, which is brought about by the activation of DHPRs. Further, cardiac muscle tend to exhibit dyad structures, rather than triads.

  1. An action potential is initiated by pacemaker cells in the Sinoatrial node or Atrioventricular node and conducted to all cells in the heart via gap junctions.
  2. The action potential travels along the surface membrane into T-tubules (the latter are not seen in all cardiac cell types) and the depolarisation causes Ca2+
    to enter the cell via L-type calcium channels and possibly sodium-calcium exchanger during the early part of the plateau phase. This Ca2+
    influx causes a small local increase in intracellular Ca2+
    .
  3. The increase in Ca2+
    is detected by ryanodine receptors in the membrane of the sarcoplasmic reticulum which releases Ca2+
    in a positive feedback physiological response. This positive feedback is known as calcium-induced calcium release and gives rise to Calcium sparks (Ca2+
    sparks[3]).
  4. The spatial and temporal summation of ~30,000 Ca2+
    sparks gives a cell-wide increase in cytoplasmic calcium concentration.[4]
  5. The cytoplasmic calcium binds to Troponin C, moving the tropomysin complex off the actin binding site allowing the myosin head to bind to the actin filament. From this point on the contractile mechanism is essentially the same as for skeletal muscle (above). Briefly:
  6. Using ATP hydrolysis the myosin head pulls the actin filament toward the centre of the sarcomere.
  7. Intracellular calcium is taken up by the sarco/endoplasmic reticulum ATPase pump back into the sarcoplasmic reticulum ready for the next cycle to begin. Calcium is also ejected from the cell mainly by the sodium-calcium exchanger and, to a lesser extent, a plasma membrane calcium ATPase and/or taken up by the mitochondria.[5]
  8. Intracellular calcium concentration drops and troponin complex returns over the active site of the actin filament, ending contraction.

Smooth muscle[edit]

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).

See also[edit]

References[edit]

  1. ^ Sandow A (1952). "Excitation-Contraction Coupling in Muscular Response". Yale J Biol Med 25 (3): 176–201. PMC 2599245. PMID 13015950. 
  2. ^ Fabiato, A. (1983). "Calcium-induced calcium release from the cardiac sarcoplasmic reticulum". American Journal of Physiology 245 (1): C1–14. PMID 6346892. 
  3. ^ Cheng H, Lederer WJ, Cannell MB (October 1993). "Calcium sparks: elementary events underlying excitation-contraction coupling in heart muscle". Science 262 (5134): 740–4. doi:10.1126/science.8235594. PMID 8235594. 
  4. ^ Cannell MB, Cheng H, Lederer WJ (November 1994). "Spatial non-uniformities in Ca2+
    i during excitation-contraction coupling in cardiac myocytes"
    . Biophys. J. 67 (5): 1942–56. doi:10.1016/S0006-3495(94)80677-0. PMC 1225569. PMID 7858131.
     
  5. ^ Crespo LM, Grantham CJ, Cannell MB (June 1990). "Kinetics, stoichiometry and role of the Na-Ca exchange mechanism in isolated cardiac myocytes". Nature 345 (6276): 618–21. doi:10.1038/345618a0. PMID 2348872.