A mutation in the ryanodine receptor has been shown to cause malignant hyperthermia (MH), a potentially fatal response to volatile anesthetics. Mutations in this gene only cause MH in about 20% of affected human families. We have isolated and mapped two mutations,
fc20(V) and
fc34(V), which cause MH-like responses to volatile anesthetics and which do not involve the ryanodine receptor. Although nearly normal in motion in air, in all volatile anesthetics, 100% of both mutant strains contract and prolonged exposure is lethal to both.
fc20 and
fc34 are downstream from previously identified mutations in a genetic pathway controlling sensitivity to volatile anesthetics, making them ideal candidates to directly associate with contractile responses in muscle. Under conditions of stress (starvation), about 10-20% of the
fc34 animals contract, while 5-10% of the
fc20 animals do so. If calcium is removed from the plate, all
fc34 animals contract dramatically; no such response is seen with
fc20. We tested the responses of
fc20,
fc34 and N2 to caffeine. In 5mM caffeine, 30% of
fc20 worms contracted (the remainder had a strong twitching response), 80% of
fc34 contracted, and N2 was unaffected. At 40mM caffeine, N2 was also immobilized, but did not contract. We tested the effects of dantrolene (a calcium channel blocker) on
fc20 and
fc34. The immobility seen at low doses of halothane was not reversed. However, the contractures greatly lessened; thus, as in MH, dantrolene specifically alleviates the contractile response. The responses of
fc34 and
fc20 to volatile anesthetics, caffeine, dantrolene and calcium changes are all consistent with the hypothesis that these alleles represent models for the MH state. They may be the only physiologic probes for MH not caused by changes in the ryanodine receptor.