Modulation of inositol trisphosphate (InsP₃) receptor (InsP₃R) activity by isoflurane and the effects on cell survival. Isoflurane can activate InsP₃R or potentiate the activation of InsP₃R by endogenous agonist InsP₃ generated by various extracellular stimulation including antibody for immunoglobulin M (IgM Ab). These effects can be inhibited by InsP₃R antagonists xestospongin and heparin. Moderate activation of InsP₃R by isoflurane at low concentration for short duration causes moderate Ca²⁺ release from the endoplasmic reticulum (ER) and increase of cytosolic Ca²⁺, which in turn, inhibit cell death by inducing endogenous cytoprotective mechanisms (left side), such as activation of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)-protein kinase B (AKT) and microtubule-associated protein kinase (MAPK)/extracellular-signal-regulated kinases (ERK) pathways. Excessive activation of InsP₃R by isoflurane at high concentration for prolonged duration causes excessive Ca²⁺ release from the ER and abnormal increase of cytosolic Ca²⁺, resulting in induction of cell death via apoptosis directly (right side), through rerelease of cytochrome C (Cyc C) from mitochondria into cytosolic space. ATP = adenosine triphosphate.