Ewing sarcoma cells exploit the IL1RAP-CTH axis to drive oxidative stress adaptation and lung metastasis

Inositol 1,4,5-trisphosphate (IP3) and cyclic adenosine diphosphate-ribose (cADPR) are second messengers that enhance neurosecretion by inducing Ca2+ release from smooth endoplasmic reticulum (SER). The putative intracellular messenger, nicotinic acid adenine dinucleotide phosphate (NAADP), releases Ca2+ from stores that are distinct from SER. Evidence is presented here that NAADP causes a concentration-dependent increase in quantal output that is associated with an increase in probability of transmitter release at the frog neuromuscular junction. This effect is mimicked by A23187, a Ca ionophore that promotes Ca2+ entry at the plasmalemma. The response to NAADP is potentiated by IP3 but antagonized by cADPR. Thapsigargin completely blocks IP3 and cADPR responses and decreases but does not prevent the response to NAADP. We conclude that NAADP, whose receptors are widely distributed in the brain, enhances neurosecretion by releasing Ca2+ from an internal store near the plasmalemma, possibly from synaptic vesicles in the releasable pool. These data also support the hypothesis of a two-pool model for Ca2+oscillations at the presynaptic site.