Figure 7.

Proposed mechanism for OPRM1-mediated d,l-methadone-induced apoptosis in leukemic cells. (A) Previously, stimulation of an unidentified type of opioid receptor (#) by d,l-methadone was shown to induce leukemic cell death via G_αi, which blocks adenylyl cyclase activity that in turn reduces [cAMP]_i, activating caspase-9 and -3⁵. (B) In the current study, we identify the OPRM1 opioid receptor as a specific d,l-methadone target in leukemic cells. Since activation of opioid receptors has been shown to cause G_βγ-mediated rise in [Ca²⁺]_i via PLC^22,26–28, we propose that d,l-methadone activation of OPRM1 in leukemic cells causes G_βγ-mediated stimulation of PLC, which then triggers a rise in [Ca²⁺]_i through increased IP3R-mediated ER Ca²⁺ release and reduced rate of Ca²⁺ efflux, causing upregulation of the Ca²⁺-mediated calpain-1-Bid-cyt C-caspase-3/12 apoptotic pathway and subsequent apoptosis.