cGMP inhibits GTP cyclohydrolase I activity and biosynthesis of tetrahydrobiopterin in human umbilical vein endothelial cells

Hiroaki Shiraishi, Taiya Kato, Koji Atsuta, Chiho Sumi-Ichinose, Masatsugu Ohtsuki, Mitsuyasu Itoh, Hitoshi Hishida, Shin Tada, Yasuhiro Udagawa, Toshiharu Nagatsu, Yasumichi Hagino, Hiroshi Ichinose, Takahide Nomura

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7 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)265-271
Number of pages7
JournalJournal of Pharmacological Sciences
Volume93
Issue number3
DOIs
Publication statusPublished - 01-11-2003

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

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    Shiraishi, H., Kato, T., Atsuta, K., Sumi-Ichinose, C., Ohtsuki, M., Itoh, M., Hishida, H., Tada, S., Udagawa, Y., Nagatsu, T., Hagino, Y., Ichinose, H., & Nomura, T. (2003). cGMP inhibits GTP cyclohydrolase I activity and biosynthesis of tetrahydrobiopterin in human umbilical vein endothelial cells. Journal of Pharmacological Sciences, 93(3), 265-271. https://doi.org/10.1254/jphs.93.265