In a large proportion (50–70%) of cases, the propensity for malignant hyperthermia is due to a mutation of the ryanodine receptor (type 1), located on the sarcoplasmic reticulum (SR), the organelle within skeletal muscle cells that stores calcium. RYR1 opens in response to increases in intracellular level mediated by L-type calcium channels, thereby resulting in a drastic increase in intracellular calcium levels and muscle contraction. RYR1 has two sites believed to be important for reacting to changing concentrations: the A-site and the I-site. The A-site is a high affinity binding site that mediates RYR1 opening. The I-site is a lower affinity site that mediates the protein's closing. Caffeine, halothane, and other triggering agents act by drastically increasing the affinity of the A-site for and concomitantly decreasing the affinity of the I-site in mutant proteins. also affect RYR1 activity, causing the protein to close by acting at either the A- or I-sites. In MH mutant proteins, the affinity for at either one of these sites is greatly reduced. The end result of these alterations is greatly increased release due to a lowered activation and heightened deactivation threshold. The process of sequestering this excess consumes large amounts of adenosine triphosphate (ATP), the main cellular energy carrier, and generates the excessive heat (hyperthermia) that is the hallmark of the disease. The muscle cell is damaged by the depletion of ATP and possibly the high temperatures, and cellular constituents "leak" into the circulation, including potassium, myoglobin, creatine, phosphate and creatine kinase.