Disease mechanism In a large proportion (50–70%) of cases, the propensity for<unk>  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<unk>  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<unk>  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. The other known causative gene for<unk>  is CACNA1S, which encodes an L-type voltage-gated calcium channel α-subunit. There are two known mutations in this protein, both affecting the same residue, R1086. This residue is located in the large intracellular loop connecting domains 3 and 4, a domain possibly involved in negatively regulating RYR1 activity. When these mutant channels are expressed in human embryonic kidney (HEK 293) cells, the resulting channels are five times more sensitive to activation by caffeine (and presumably halothane) and activate at 5–10mV more hyperpolarized. Furthermore, cells expressing these channels have an increased basal cytosolic concentration. As these channels interact with and activate RYR1, these alterations result in a drastic increase of intracellular , and, thereby, muscle excitability. Other mutations causing<unk>  have been identified, although in most cases the relevant gene remains to be identified. Animal model Research into<unk>  was limited until the discovery of "porcine stress syndrome" (PSS) in Danish Landrace and other pig breeds selected for muscling, a condition in which stressed pigs develop "pale, soft, exudative" flesh (a manifestation of the effects of<unk>  rendering their meat less marketable at slaughter. This "awake triggering" was not observed in humans, and initially cast doubts on the value of the animal model, but subsequently, susceptible humans were discovered to "awake trigger" (develop<unk>  in stressful situations. This supported the use of the pig model for research. Pig farmers use halothane cones in swine yards to expose piglets to halothane. Those that die were<unk> -susceptible, thus saving the farmer the expense of raising a pig whose meat he would not be able to market. This also reduced the use of breeding stock carrying the genes for PSS. The condition in swine is also due to a defect in ryanodine receptors. Gillard et al. discovered the causative mutation in humans only after similar mutations had first been described in pigs. Horses also suffer from<unk> . A causative mutated allele, ryanodine receptor 1 gene (RyR1) at nucleotide C7360G, generating a R2454G amino acid substitution. has been identified in the American Quarter Horse and breeds with Quarter Horse ancestry, inherited as an autosomal dominant. It can be caused by overwork, anesthesia, or stress. In dogs, its inheritance is autosomal recessive. An<unk>  mouse has been constructed, bearing the R163C mutation prevalent in humans. These mice display signs similar to human<unk>  patients, including sensitivity to halothane (increased respiration, body temperature, and death). Blockade of RYR1 by dantrolene prevents adverse reaction to halothane in these mice, as with humans. Muscle from these mice also shows increased -induced depolarization and an increased caffeine sensitivity.
Malignant hyperthermia
Sepsis
Hypothermia
Serotonin syndrome
Hyperthermia
Neuroleptic malignant syndrome
Nitrogen narcosis
Anaphylaxis