In malignant hyperthermia (MH) susceptible individuals, skeletal muscle contraction across the body is triggered by inhalational anaesthetics such as halothane. MH has been linked with hundreds of genetically-dominant RyR1 missense variants, although only 47 have been demonstrated to be definitively causative so far. The ryanodine receptor, RyR1, is the ion channel mediating release of Ca2+ from the sarcoplasmic reticulum to elicit skeletal muscle contraction. The RyR1 missense variants appear to modify the opening of the channel during both triggered and resting states. C. elegans has one ryanodine receptor gene,
unc-68. C. elegans strains with single UNC-68 amino acid residue changes equivalent to those of 8 MH associated RyR1 variants, all had increased sensitivity to halothane. In a genetic screen, mutations in
cla-1 were found which further enhanced the increased halothane sensitivity of one of these C. elegans strains, that representing the RyR1 A4940T variant. This genetic interaction was confirmed with independent
cla-1 deletions. CLA-1, however, is an active zone protein involved in neurotransmitter release and is not thought to be expressed in muscle cells. That the
unc-68 missense mutations might be perturbing a presynaptic function of the ryanodine receptor was subsequently supported by the responses to aldicarb and levamisole, even in the absence of the halothane challenge. There are three mammalian RYR genes. RYR3 is seen as encoding the neuronal isoform although all three are expressed in nerve cells. There are also hundreds of RyR3 variants in the human population, many with residues modified as for MH associated RyR1 variants, although none have been firmly linked to human pathology. Conservation, from human RyR1 to C. elegans UNC-68, of both the MH associated variant residues and the biological consequences of their replacement, along with our findings, suggests that existing RyR1 and RyR3 variants may affect human nerve cell function, even in the absence of a triggering agent. Subtle, but constitutive, disturbance of Ca2+ balance in nerve cells due to ryanodine receptor variants could have chronic, rather than acute, neuropathological effects.