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Research ArticleArticle

Differential Regulation of Peptide α-Amidation by Dexamethasone and Disulfiram

William J. Driscoll, S. Alyssa Mueller, Betty A. Eipper and Gregory P. Mueller
Molecular Pharmacology June 1999, 55 (6) 1067-1076; DOI: https://doi.org/10.1124/mol.55.6.1067
William J. Driscoll
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S. Alyssa Mueller
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Betty A. Eipper
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Gregory P. Mueller
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Abstract

α-Amidation is essential for the function of many peptides in intercellular communication. This C-terminal modification is mediated in a two-step process by the hydroxylase and lyase activities of the bifunctional enzyme, peptidylglycine α-amidating monooxygenase (PAM). The first step, catalyzed by peptidylglycine-α-hydroxylating monooxygenase (PHM; EC 1.14.17.3), is rate limiting in the process, and therefore subject to regulation. Dexamethasone and disulfiram (tetraethylthiuram disulfide; Antabuse) were used as in vivo treatments to study the regulation of PHM expression and activity in cardiac atrium. Our findings show that both dexamethasone and disulfiram treatment increase the activity of PHM in atrial tissue but that they do so by distinctly different mechanisms. Dexamethasone elevated tissue levels of PAM mRNA and protein concurrently, suggesting that glucocorticoids regulate PAM expression at the level of gene transcription. In contrast, disulfiram treatment, which depletes stores of α-amidated peptides, increased the specific activity of PHM without affecting the level of PAM expression. The catalytic efficiency of PHM was enhanced by raising the V max of the enzyme. Importantly, this increase inV max was retained through purification to homogeneity, indicating that either a covalent modification or a stable conformational change had occurred in the protein. These novel findings demonstrate that the rate-limiting enzyme in the bioactivation of peptide messengers is differentially regulated by transcriptional and post-transcriptional mechanisms in vivo. It is proposed that regulation of PHM’s expression and catalytic efficiency serve as coordinated physiologic mechanisms for maintaining appropriate levels of α-amidating activity under changing conditions in vivo.

Footnotes

    • Received November 13, 1999.
    • Accepted February 26, 1999.
  • Send reprint requests to: Dr. Gregory P. Mueller, Department of Physiology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD 20814-4799. E-mail:gmueller{at}USUHS.mil

  • This work was supported by National Institutes of Health Grants NS34173 (to G.P.M.) and DK32949 (to B.A.E) and Uniformed Services University of the Health Sciences Grant RO7644 (G.P.M.).

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 55 (6)
Molecular Pharmacology
Vol. 55, Issue 6
1 Jun 1999
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Research ArticleArticle

Differential Regulation of Peptide α-Amidation by Dexamethasone and Disulfiram

William J. Driscoll, S. Alyssa Mueller, Betty A. Eipper and Gregory P. Mueller
Molecular Pharmacology June 1, 1999, 55 (6) 1067-1076; DOI: https://doi.org/10.1124/mol.55.6.1067

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Research ArticleArticle

Differential Regulation of Peptide α-Amidation by Dexamethasone and Disulfiram

William J. Driscoll, S. Alyssa Mueller, Betty A. Eipper and Gregory P. Mueller
Molecular Pharmacology June 1, 1999, 55 (6) 1067-1076; DOI: https://doi.org/10.1124/mol.55.6.1067
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