A possible role for inositol 1,4,5-trisphosphate (IP3) in malignant hyperthermia.
In Malignant Hyperthermia an increased open probability of the ryanodine Ca(2+)-channels in the SR-membrane primes a higher cytosolic Ca(2+)-concentration. This in turn accelerates ATP-hydrolysis culminating in a gradual decrease in ATP-levels. At low ATP-levels, IP3-synthesis is being stimulated and the ability of IP3 to release Ca2+ is enhanced. This results through the opening of IP3-dependent channels. Ca(2+)-release through the ryanodine channels and the IP3-dependent channels summate to increase the cytosol Ca(2+)-levels to such a high value that ATP is hydrolysed below a critical value causing rigor (contracture) of skeletal muscle. Since Ca(2+)-uptake by the SR is ATP-dependent, Ca(2+)-uptake will eventually also slow down and so contributes to the rise in cytosol Ca(2+)-concentration.
Steinmann
C M
CM
Dept Physiology, University of Pretoria, South Africa.
D000255:Adenosine Triphosphate / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008305:Malignant Hyperthermia / Q000209:etiology* / Q000378:metabolism; D008954:Models, Biological; D009119:Muscle Contraction / Q000502:physiology; D009124:Muscle Proteins / Q000378:metabolism; D009132:Muscles / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel
D015220:Calcium Channels; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D009124:Muscle Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D019837:Ryanodine Receptor Calcium Release Channel; D015544:Inositol 1,4,5-Trisphosphate; D000255:Adenosine Triphosphate; D002118:Calcium