Nitric oxide-induced mobilization of intracellular calcium via the cyclic ADP-ribose signaling pathway

Willmott, Nick, Sethi, Jaswinder K., Walseth, Timothy P., Lee, Hon Cheung, White, Alison M. and Galione, Antony (1996) Nitric oxide-induced mobilization of intracellular calcium via the cyclic ADP-ribose signaling pathway. The Journal of Biological Chemistry, 271 (7), 3699-3705. (doi:10.1074/jbc.271.7.3699).

Abstract

Cyclic adenosine diphosphate ribose (cADPR) is a potent endogenous calcium-mobilizing agent synthesized from β-NAD⁺ by ADP-ribosyl cyclases in sea urchin eggs and in several mammalian cells (Galione, A., and White, A. (1994) Trends Cell Biol. 4, 431-436). Pharmacological studies suggest that cADPR is an endogenous modulator of Ca²⁺-induced Ca²⁺ release mediated by ryanodine-sensitive Ca²⁺ release channels. An unresolved question is whether cADPR can act as a Ca²⁺-mobilizing intracellular messenger. We show that exogenous application of nitric oxide (NO) mobilizes Ca²⁺ from intracellular stores in intact sea urchin eggs and that it releases Ca²⁺ and elevates cADPR levels in egg homogenates. 8-Amino-cADPR, a selective competitive antagonist of cADPR-mediated Ca²⁺ release, and nicotinamide, an inhibitor of ADP-ribosyl cyclase, inhibit the Ca²⁺-mobilizing actions of NO, while, heparin, a competitive antagonist of the inositol 1,4,5- trisphosphate receptor, did not affect NO-induced Ca²⁺ release. Since the Ca²⁺-mobilizing effects of NO can be mimicked by cGMP, are inhibited by the cGMP-dependent-protein kinase inhibitor, R(p)-8-pCPT-cGMPS, and in egg homogenates show a requirement for the guanylyl cyclase substrate, GTP, we suggest a novel action of NO in mobilizing intracellular calcium from microsomal stores via a signaling pathway involving cGMP and cADPR. These results suggest that cADPR has the capacity to act as a Ca²⁺-mobilizing intracellular messenger.

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Contributors

Author: Jaswinder K. Sethi

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