Guanosine triphosphate cyclohydrolase i expression and enzymatic activity are present in caveolae of endothelial cells

Timothy E. Peterson, Livius V. D'Uscio, Sheng Cao, Xiao Li Wang, Zvonimir S. Katusic

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Tetrahydrobiopterin is an essential cofactor required for the synthesis of NO. GTP cyclohydrolase I (GTPCH I) is the rate-limiting enzyme for tetrahydrobiopterin production in endothelial cells, yet little is known about the subcellular localization of this enzyme. In this study, we demonstrated that GTPCH I is localized to caveolar membrane microdomains along with caveolin-1 and endothelial NO synthase. GTPCH I activity was detected in isolated caveolar membranes from cultured endothelial cells. Confocal and electron microscopy analyses confirmed GTPCH I colocalization with caveolin-1. Consistent with in vitro studies, GTPCH I activity was evident in isolated caveolar microdomains from lung homogenates of wild-type mice. Importantly, a 2-fold increase in GTPCH I activity was detected in the aortas of caveolin-1-deficient mice, suggesting that caveolin-1 may be involved in the control of GTPCH I enzymatic activity. Indeed, overexpression of caveolin-1 inhibits GTPCH I activity, and tetrahydrobiopterin biosynthesis is activated by the disruption of caveolae structure. These studies demonstrate that GTPCH I is targeted to caveolae microdomains in vascular endothelial cells, and tetrahydrobiopterin production occurs in close proximity to endothelial NO synthase. In addition, our findings provide new insights into the regulation of GTPCH I activity by the caveolar coat protein, caveolin-1

Original languageEnglish (US)
Pages (from-to)189-195
Number of pages7
JournalHypertension
Volume53
Issue number2
DOIs
StatePublished - Feb 2009

Keywords

  • Caveolin-1
  • Endothelium
  • Gtp-cyclohydrolase i
  • Nitric oxide
  • Tetrahydrobiopterin

ASJC Scopus subject areas

  • Internal Medicine

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