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.