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Randen L. Patterson *,
Damian B. van Rossum *,
Adam I. Kaplin *,
Roxanne K. Barrow *, and
Solomon H. Snyder *, , , ¶
*Departments of Neuroscience, Pharmacology and Molecular Sciences, and Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205
Contributed by Solomon H. Snyder, December 22, 2004
NADH regulates the release of calcium from the endoplasmic reticulumby modulation of inositol 1,4,5-trisphosphate receptors (IP3R),accounting for the augmented calcium release of hypoxic cells.We report selective binding of IP3R to GAPDH, whose activityleads to the local generation of NADH to regulate intracellularcalcium signaling. This interaction requires cysteines 992 and995 of IP3R and C150 of GAPDH. Addition of native GAPDH andNAD+ to WT IP3R stimulates calcium release, whereas no stimulationoccurs with C992S/995S IP3R that cannot bind GAPDH. Thus, theIP3R/GAPDH interaction likely enables cellular energy dynamicsto impact calcium signaling.