Malignant hyperthermia due to abnormal regulation of a calcium channel in muscle cells

Malignant hyperthermia is a severe, lifethreatening
complication of anesthesia that
may occur in persons with extreme hypersensitivity
to halothane and similar agents used in
general anesthesia. Normally, a nerve impulse
depolarizes the plasma membrane of a nerve
ending at the nerve–muscle endplate (1)
(motor endplate), and the volt-gated calcium
channel in the plasma membrane of the nerve
ending is temporarily opened. The massive influx
of calcium into the cell (the extracellular
Ca2 + concentration is about 1000 times higher
than the intracellular) triggers the release of
acetylcholine. Binding of the latter to the acetylcholine
receptor of the muscle cell temporarily
opens the receptor-controlled cation (Na+)
channels. This opens calcium channels located
in the sarcoplasmic reticulum of the muscle
cell. The resulting rapid increase in Ca2 +
concentration in the cytosol causes the myofibrils
in the muscle cell to contract. The calcium
channels in the sarcoplasmic reticulum are
regulated by a receptor (ryanodin receptor) (2).
Ryanodin (an alkaloid) binds to the calcium
channel. The ryanodin receptor is a protein with
four transmembrane domains. Mutations in the
ryanodin receptor lead to greatly increased sensitivity
to halothane and other anesthetic
agents (3), which cause muscle spasm, drastic
elevation of temperature (hyperthermia), acidosis,
and cardiac arrest (4). Malignant hyperthermia
is inherited as an autosomal dominant
trait (5). One gene in man lies on chromosome
19 at 19q13.1 (MacLennan and Phillips, 1992).
Additional loci are on 7q, 17q, and 3q13.1 (Subrak
et al., 1995). The mutant haplotype of a
given family can be determined by segregation
analysis. A ryanodin receptor mutation has
been demonstrated in porcine malignant hyperthermia.