cGMP Inhibits GTP Cyclohydrolase I Activity and Biosynthesis of Tetrahydrobiopterin in Human Umbilical Vein Endothelial Cells

Journal of Pharmacological Sciences

Chiho Sumi-Ichinose⁴  Masatsugu Ohtsuki²  Mitsuyasu Itoh²  Toshiharu Nagatsu¹  Hitoshi Hishida²  Yasuhiro Udagawa³  Shin Tada³  Hiroaki Shiraishi⁴  Koji Atsuta⁴  Taiya Kato²  Hiroshi Ichinose¹  Takahide Nomura⁴  Yasumichi Hagino⁴ 

[1] Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University;Department of Internal Medicine, School of Medicine, Fujita Health University;Department of Obstetrics and Gynecology, School of Medicine, Fujita Health University;Department of Pharmacology, School of Medicine, Fujita Health University

关键词: GTP cyclohydrolase I;    tetrahydrobiopterin;    nitric oxide;    endothelial cell;    cGMP;   

DOI  :  10.1254/jphs.93.265

学科分类：药学

来源: Nihon Yakuri Gakkai Henshuubu / Japanese Pharmacological Society

【 摘 要 】

References(35)Cited-By(5)Tetrahydrobiopterin (BH4) acts as an essential cofactor for the enzymatic activity of nitric oxide (NO) synthases. Biosynthesis of the cofactor BH4 starts from GTP and requires 3 enzymatic steps, which include GTP cyclohydrolase I (GCH I) catalysis of the first and rate-limiting step. In this study we examined the effects of cGMP on GCH I activity in human umbilical vein endothelial cells under inflammatory conditions. Exogenous application of the cGMP analogue 8-bromo-cGMP markedly inhibited GCH I activity in the short term, whereas an cAMP analogue had no effect on GCH I activity under the same condition. NO donors, NOR3 and sodium nitroprusside, elevated the intracellular cGMP level and reduced GCH I activity in the short term. This inhibition of GCH I activity was obliterated in the presence of an NO trapper carboxy-PTIO. NO donors had no effect on GCH I mRNA expression in the short term. Moreover, cycloheximide did not alter the inhibition by NO donors of GCH I activity. These findings suggest that stimulation of the cGMP signaling cascade down-regulates GCH I activity through post translational modification of the GCH I enzyme.

【 授权许可】

Unknown