Effects of MH triggers on Ca2+release. A: Uncontrolled myoplasmic Ca2+ release is the key to malignant hyperthermia. The most prominent cytosolic Ca2+ elevation results from the freeing of stored sarcoplasmic Ca2+ mediated by ryanodine receptor type 1 (RyR1). While volatile anesthetics stimulate Ca2+ release via RyR1, succinylcholine acts indirectly by activating the nicotinergic acetylcholine receptor (nAChR), a nonspecific cation channel, resulting in continuous local depolarisation. The depolarization can trigger propagated action potentials and will further activate the dihydropyridine receptors (DHPR, CaV1.1) leading to the gating of both Ca2+ release from the SR via RyR1 and L-type Ca2+ current from the extracellular space. B: Heavy SR from rat muscle was maximally preloaded with Ca2+ before testing the potential Ca2+ releasing agonists halothane, isoflurane, enflurane and succinylcholine. The resulting Ca2+ release is via the RyR1 channel. Halothane, isoflurane and enflurane induced Ca2+ release from the SR vesicles but succinylcholine had no detectable effect. Results are expressed as mean ± standard error from six separate SR specimens. Of the three anesthetics tested, halothane showed the greatest potency and efficacy.* C: Succinylcholine (SCh) significantly increases halothane induced contractures in malignant hyperthermia susceptible individuals. However, SCh alone does not lead to the development of pathological contractures in MHN or MHS individuals*. *Part of the data from Figure 1B and C was published in Klingler et al. in 2005 .