Inositol 1,4,5-trisphosphate receptor/GAPDH complex augments Ca 2+ release via locally derived NADH

NADH regulates the release of calcium from the endoplasmic reticulum by modulation of inositol 1,4,5-trisphosphate receptors (IP 3 R), accounting for the augmented calcium release of hypoxic cells. We report selective binding of IP 3 R to GAPDH, whose activity leads to the local generation of NADH to regulate intracellular calcium signaling. This interaction requires cysteines 992 and 995 of IP 3 R and C150 of GAPDH. Addition of native GAPDH and NAD + to WT IP 3 R stimulates calcium release, whereas no stimulation occurs with C992S/995S IP 3 R that cannot bind GAPDH. Thus, the IP 3 R/GAPDH interaction likely enables cellular energy dynamics to impact calcium signaling.