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

Research output: Contribution to journalArticle

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

Fingerprint

GTP Cyclohydrolase
Human Umbilical Vein Endothelial Cells
Nitric Oxide Donors
sapropterin
Nitroprusside
Cycloheximide
Post Translational Protein Processing
Guanosine Triphosphate
Catalysis
Nitric Oxide Synthase
Nitric Oxide
Down-Regulation

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

Shiraishi, Hiroaki ; Kato, Taiya ; Atsuta, Koji ; Sumi-Ichinose, Chiho ; Ohtsuki, Masatsugu ; Itoh, Mitsuyasu ; Hishida, Hitoshi ; Tada, Shin ; Udagawa, Yasuhiro ; Nagatsu, Toshiharu ; Hagino, Yasumichi ; Ichinose, Hiroshi ; Nomura, Takahide. / cGMP inhibits GTP cyclohydrolase I activity and biosynthesis of tetrahydrobiopterin in human umbilical vein endothelial cells. In: Journal of Pharmacological Sciences. 2003 ; Vol. 93, No. 3. pp. 265-271.
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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.",
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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, vol. 93, no. 3, pp. 265-271. https://doi.org/10.1254/jphs.93.265

cGMP inhibits GTP cyclohydrolase I activity and biosynthesis of tetrahydrobiopterin in human umbilical vein endothelial cells. / Shiraishi, Hiroaki; Kato, Taiya; Atsuta, Koji; Sumi-Ichinose, Chiho; Ohtsuki, Masatsugu; Itoh, Mitsuyasu; Hishida, Hitoshi; Tada, Shin; Udagawa, Yasuhiro; Nagatsu, Toshiharu; Hagino, Yasumichi; Ichinose, Hiroshi; Nomura, Takahide.

In: Journal of Pharmacological Sciences, Vol. 93, No. 3, 01.11.2003, p. 265-271.

Research output: Contribution to journalArticle

TY - JOUR

T1 - cGMP inhibits GTP cyclohydrolase I activity and biosynthesis of tetrahydrobiopterin in human umbilical vein endothelial cells

AU - Shiraishi, Hiroaki

AU - Kato, Taiya

AU - Atsuta, Koji

AU - Sumi-Ichinose, Chiho

AU - Ohtsuki, Masatsugu

AU - Itoh, Mitsuyasu

AU - Hishida, Hitoshi

AU - Tada, Shin

AU - Udagawa, Yasuhiro

AU - Nagatsu, Toshiharu

AU - Hagino, Yasumichi

AU - Ichinose, Hiroshi

AU - Nomura, Takahide

PY - 2003/11/1

Y1 - 2003/11/1

N2 - 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.

AB - 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.

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