Endogenous Nitric Oxide Generation Linked to Ryanodine Receptors Activates Cyclic GMP / Protein Kinase G Pathway for Cell Proliferation of Neural Stem/Progenitor Cells Derived From Embryonic Hippocampus

Journal of Pharmacological Sciences

Kiyokazu Ogita¹  Masanori Yoneyama¹  Tatsuo Shiba¹  Koichi Kawada¹ 

[1] Department of Pharmacology, Setsunan University Faculty of Pharmaceutical Sciences, Japan

关键词: cyclic GMP / protein kinase G pathway;    neural stem/progenitor cells;    nitric oxide;    proliferation;    ryanodine receptor channel;   

DOI  :  10.1254/jphs.10290FP

学科分类：药学

来源: Nihon Yakuri Gakkai Henshuubu / Japanese Pharmacological Society

【 摘 要 】

References(46)Cited-By(13)Nitric oxide (NO) activates the cyclic GMP (cGMP) / protein kinase G (PKG) pathway during physiological processes in numerous types of cells. Here, we evaluated whether this NO/cGMP/PKG pathway is involved in the proliferation of neural stem/progenitor cells (NPCs) derived from the hippocampus of embryonic mice. In culture, the exposure to the NO synthase inhibitor Nω-nitro-L-arginine methyl ester (L-NAME) significantly decreased the number of viable cells and 5-bromo-2′-deoxyuridine (BrdU) incorporation into the cells, as well as the levels of intracellular reactive oxygen species, extracellular NO2, and intracellular cGMP. Like L-NAME, the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and PKG inhibitor KT5823 also decreased cell viability and BrdU incorporation. The membrane-permeable cGMP analogue 8-bromo-cGMP partially abolished the L-NAME–induced decrease in the BrdU incorporation. BrdU incorporation was decreased by Ca2+-channel blockers, including dantrolene, MK-801, ifenprodil, and nifedipine. Interestingly, the NO2 level was decreased by dantrolene, but not by the other 3 blockers. L-NAME and ODQ attenuated phosphorylation of Akt, but not that of extracellular signal-regulated kinases or epidermal growth factor receptors. Our data suggest that endogenous NO generation linked to dantrolene-sensitive ryanodine receptors activates the cGMP/PKG signaling pathway for positive regulation of proliferation of hippocampal NPCs derived from embryonic mice.

【 授权许可】

Unknown