RT Journal Article
SR Electronic
T1 Reduced nicotinamide adenine dinucleotide-selective stimulation of inositol 1,4,5-trisphosphate receptors mediates hypoxic mobilization of calcium
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 2002
OP 2011
DO 10.1523/JNEUROSCI.16-06-02002.1996
VO 16
IS 6
A1 AI Kaplin
A1 SH Snyder
A1 DJ Linden
YR 1996
UL http://www.jneurosci.org/content/16/6/2002.abstract
AB To evaluate the relationship of inositol 1,4,5-trisphosphate (IP3) receptor-mediated signal transduction and cellular energy dynamics, we have characterized effects of nucleotides on IP3 receptor (IP3R)- mediated calcium (Ca2+) flux in purified IP3 receptors reconstituted in lipid vesicles (IP3RV) and examined hypoxia-induced augmentation of intracellular Ca2+ in intact cells. Reduced nicotinamide adenine dinucleotide (NADH) increases IP3-mediated Ca2+ flux in IP3RV. This effect is highly specific for NADH. Hypoxia elicited by brief exposure of nerve growth factor-differentiated PC12 cells or cerebellar Purkinje cells to cyanide elicits rapid increased in internal [Ca2+], which derives from IP3-sensitive stores. Blockade of this effect by 2- deoxyglucose and inhibition of glyceraldehyde-3-phosphate dehydrogenase implicates enhanced glycolytic production of NADH in the Ca2+ stimulation. Internal [Ca2+] is markedly and specifically increased by direct intracellular injection of NADH, and this effect is blocked by heparin, further implicating IP3R stores. These findings indicate that direct regulation of IP3R by NADH is responsible for elevated cytoplasmic [Ca2+] occurring in the earliest phase of hypoxia. This link of IP3R activity with cellular energy dynamics may be relevant to both hypoxic damage and metabolic regulation of IP3 signaling processes.