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

Hiroaki Shiraishi, Taiya Kato, Koji Atsuta, Chiho 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 ; 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.",
author = "Hiroaki Shiraishi and Taiya Kato and Koji Atsuta and Chiho Ichinose and Masatsugu Ohtsuki and Mitsuyasu Itoh and Hitoshi Hishida and Shin Tada and Yasuhiro Udagawa and Toshiharu Nagatsu and Yasumichi Hagino and Hiroshi Ichinose and Takahide Nomura",
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Shiraishi, H, Kato, T, Atsuta, K, 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; 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 - 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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DO - 10.1254/jphs.93.265

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