Interaction of human GTP cyclohydrolase I with its splice variants

Pandya, Maya J.; Golderer, Georg; Werner, Ernst R.; Werner-Felmayer, Gabriele

doi:10.1042/bj20060765

Cited by 13 publications

(15 citation statements)

References 34 publications

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“…The second mechanism is through suppressing translation of full-length α ENaC more prominently in Dahl R versus S rats. The third mechanism is via an enhanced binding of α ENaC-b protein to the full-length α ENaC and accelerated degradation of the latter as a result of direct binding to α ENaC-b, a phenomenon that has been reported previously in several other channels and membrane proteins [7-9,11-13]. Enhanced binding of α ENaC-b to the full-length α ENaC might trap α ENaC in the endoplasmic reticulum and/or inhibit proper ENaC assembly and trafficking to the plasma membrane, resulting in the formation of non functional channels.…”

Section: Presentation Of the Hypothesismentioning

confidence: 86%

The Epithelial Sodium Channel α subunit (α ENaC) alternatively spliced form "b" in Dahl rats: What's next?

Shehata¹

2010

Int Arch Med

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BackgroundThe amiloride-sensitive Epithelial Sodium Channel (ENaC) is critical in maintaining Na+ balance, extracellular fluid volume and long term blood pressure control. ENaC is composed of three main subunits α, β, & γ. While α ENaC is critical for channel functionality, β & γ ENaC maximize channel function. To date, there are four alternatively spliced forms of the α subunit of ENaC (α ENaC-a, -b, -c, & -d) that have been published in rats, in addition to the major α ENaC transcript. While α ENaC-a, -c & -d transcripts are low abundance transcripts compared to full-length α ENaC, α ENaC-b is a higher abundance and salt-sensitive transcript compared to full-length α ENaC.Presentation of the hypothesisα ENaC-b protein, which is preferentially produced in Dahl R rats, to a greater extent on high salt diet, exerts a dominant negative effect on full-length α ENaC subunit by physically binding to and trapping full-length α ENaC subunit in the endoplasmic reticulum, and finally accelerating full-length α ENaC proteolytic degradation in a dose-dependent manner.Testing the hypothesis1) To examine the mRNA and protein abundance of α ENaC-b relative to α ENaC full-length in kidney, lung, and taste tissues of Dahl rats. 2) To compare the expression (mRNA and protein) of α ENaC-b in kidneys of Dahl S and R rats on regular and high salt diet. 3) To examine the putative binding of α ENaC-b proteins to full-length α ENaC in vitro and to determine the impact of such binding on full-length α ENaC expression in vitro.Implications of the hypothesisOur studies will be the first to demonstrate the over-expression of salt-sensitive α ENaC-b spliced form in kidney tissues of Dahl R rats at the expense of full-length α ENaC. The current proposal will provide highly novel insights into the putative mechanisms leading to ENaC hypoactivity in high-salt-fed Dahl R rats. Finally, findings from the present proposal will uncover a new mechanism by which alternative splicing may control the regulation of ENaC expression/function.

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Section: Presentation Of the Hypothesismentioning

confidence: 86%

The Epithelial Sodium Channel α subunit (α ENaC) alternatively spliced form "b" in Dahl rats: What's next?

Shehata¹

2010

Int Arch Med

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“…Accordingly, we hypothesize that the impaired activation of GTP cyclohydrolase may represent a consequence of postmitotic maturation of cardiac myocytes coinciding with the repression of certain unknown genes or possibly increasing levels of pertinent silencing mRNA. Alternatively, splice variants of GTP cyclohydrolase have been reported that lack functional activity, thereby functioning via a dominant negative effect (13,20,41). However, it is remains unclear whether splice variants are an operative mechanism in adult cardiac myocytes.…”

Section: Discussionmentioning

confidence: 99%

Deficient BH₄production via de novo and salvage pathways regulates NO responses to cytokines in adult cardiac myocytes

Ионова¹,

Vásquez‐Vivar²,

Whitsett³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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Adult rat cardiac myocytes typically display a phenotypic response to cytokines manifested by low or no increases in nitric oxide (NO) production via inducible NO synthase (iNOS) that distinguishes them from other cell types. To better characterize this response, we examined the expression of tetrahydrobiopterin (BH4)-synthesizing and arginine-utilizing genes in cytokine-stimulated adult cardiac myocytes. Intracellular BH4 and 7,8-dihydrobiopterin (BH2) and NO production were quantified. Cytokines induced GTP cyclohydrolase and its feedback regulatory protein but with deficient levels of BH4 synthesis. Despite the induction of iNOS protein, cytokine-stimulated adult cardiac myocytes produced little or no increase in NO versus unstimulated cells. Western blot analysis under nonreducing conditions revealed the presence of iNOS monomers. Supplementation with sepiapterin (a precursor of BH4) increased BH4 as well as BH2, but this did not enhance NO levels or eliminate iNOS monomers. Similar findings were confirmed in vivo after treatment of rat cardiac allograft recipients with sepiapterin. It was found that expression of dihydrofolate reductase, required for full activity of the salvage pathway, was not detected in adult cardiac myocytes. Thus, adult cardiac myocytes have a limited capacity to synthesize BH4 after cytokine stimulation. The mechanisms involve posttranslational factors impairing de novo and salvage pathways. These conditions are unable to support active iNOS protein dimers necessary for NO production. These findings raise significant new questions about the prevailing understanding of how cytokines, via iNOS, cause cardiac dysfunction and injury in vivo during cardiac inflammatory disease states since cardiac myocytes are not a major source of high NO production.

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“…Western blot was also performed under native conditions. (3) The MAb recognized non-denaturing VSTM1-Fc protein well, but only a nonspecific band could be detected in granulocytes. (4) Specific Antigen Identified …”

Section: Igg2bmentioning

confidence: 99%

Monoclonal Antibody 2C11 Against Human VSTM1

2013

Monoclonal Antibodies in Immunodiagnosis and Immunotherapy

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Interaction of human GTP cyclohydrolase I with its splice variants

Cited by 13 publications

References 34 publications

The Epithelial Sodium Channel α subunit (α ENaC) alternatively spliced form "b" in Dahl rats: What's next?

The Epithelial Sodium Channel α subunit (α ENaC) alternatively spliced form "b" in Dahl rats: What's next?

Deficient BH₄production via de novo and salvage pathways regulates NO responses to cytokines in adult cardiac myocytes

Monoclonal Antibody 2C11 Against Human VSTM1

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Interaction of human GTP cyclohydrolase I with its splice variants

Cited by 13 publications

References 34 publications

The Epithelial Sodium Channel α subunit (α ENaC) alternatively spliced form "b" in Dahl rats: What's next?

The Epithelial Sodium Channel α subunit (α ENaC) alternatively spliced form "b" in Dahl rats: What's next?

Deficient BH4production via de novo and salvage pathways regulates NO responses to cytokines in adult cardiac myocytes

Monoclonal Antibody 2C11 Against Human VSTM1

Contact Info

Product

Resources

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Deficient BH₄production via de novo and salvage pathways regulates NO responses to cytokines in adult cardiac myocytes