Our skeletal muscles attach to the body's bony skeleton that we consciously use to perform work. To activate one of these muscles, our brain sends an electrical signal to a nerve that ends close to the muscle cell at a place called the neuromuscular junction. The electrical signal helps release a chemical (named ‘acetylcholine’), which travels across the junction to the muscle cell. This chemical attaches to special receivers (or ‘receptors’) on the muscle cell that spread current from the neuromuscular junction to the entire cell surface of the muscle. The current travels deep inside the muscle cell (via ‘transverse tubules’) to the calcium release channel (called the ‘ryanodine receptor’), the gatekeeper for the muscle cell's internal storehouse of calcium (termed the ‘sarcoplasmic reticulum’).
The calcium release channel opens, allowing calcium to flow from the storehouse to the main part (or ‘sarcoplasm’) of the muscle cell. The rising concentration of calcium triggers a sliding interaction between the thin (‘actin’) and thick (‘myosin’) fibers (or ‘filaments’) contained within the muscle cell, so that they move towards each other, thereby shortening (contracting) the muscle cell. When the calcium release channel closes, a calcium pump returns the calcium to the storehouse—the sarcoplasmic reticulum. As the calcium concentration in the sarcoplasm surrounding the actin and myosin fibers falls, the filaments slide away from one another and the muscle cell gets longer or relaxes. (See figure 5 and diagram below.)
If the calcium release channel were abnormal, it could flood a muscle cell with calcium and overpower the calcium pump. Excess calcium would prolong muscle cell contraction and cause rigidity, burn up oxygen and fuel supplies (ATP and glucose), and generate excess carbon dioxide, lactic acid, and heat from the work of contracting and as a byproduct of neutralizing the acid. Eventually, the muscle cell would be severely damaged and leak its contents including potassium and proteins normally contained with the muscle cell into the bloodstream. However, a high concentration of the MH treatment drug—dantrolene—inactivates the abnormal calcium release channel stemming the flood of excess calcium into the muscle cell.
This schematic diagram shows how a calcium release channel embedded in the sarcoplasmic reticulum membrane may open when current travels deep inside the muscle cell via the transverse tubules. The current or action potential changes the shape of a voltage sensitive protein in the transverse tubule that, in turn, helps to open the calcium release channel. Once the calcium channel opens, calcium flows from the internal storehouse of calcium into the main part of the muscle cell (or sarcoplasm) and triggers a muscle contraction. Abnormal functioning of the calcium release channel causes all known pig and some human malignant hyperthermia susceptibility. Redrawn with permission from Alberts B, Bray D, Lewis J, Raff M, Roberts K, and Watson JD, Molecular Biology of the Cell 3rd edition, Garland Publishing, 1994, New York, p. 853.
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