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Molecular Pharmacology

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Research ArticleArticle

Functionally Active Catalytic Domain Is Essential for Guanylyl Cyclase-Linked Receptor Mediated Inhibition of Human Aldosterone Synthesis

Linda J. Olson, Begonia Y. Ho, L. William Cashdollar and James G. Drewett
Molecular Pharmacology November 1998, 54 (5) 761-769; DOI: https://doi.org/10.1124/mol.54.5.761
Linda J. Olson
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Begonia Y. Ho
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L. William Cashdollar
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James G. Drewett
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Abstract

An aspartate-to-alanine point mutation in the catalytic domain (D853A) of guanylyl cyclase-C (GC-C), the heat-stable enterotoxin (STa) receptor, rendered the enzyme catalytically inactive. Mn2+/Triton X-100-stimulated guanylyl cyclase activity was detected in membranes from COS7 cells overexpressing GC-C but not GC-CD853A. STa treatment of paired cells resulted in cGMP production in those transiently expressing GC-C but not GC-CD853A. GC-C and GC-CD853A showed similar B max andK d values for [125I]STa binding in these cells, indicating that the lack of catalytic activity in the latter was not due to differing expression levels or reduced binding affinity. The involvement of the catalytic domain in aldosteronogenesis was studied in human adrenocortical H295R cells. COS7 and H295R cells infected with vaccinia virus-expressing GC-C and GC-CD853A (VVGC-CD853A) had [125I]STa-binding characteristics akin to those in transfected cells. Immunoblot confirmed that both GC-C and GC-CD853A formed similar higher order oligomers in infected cells. Virus-mediated expression of GC-C in H295R cells revealed concentration-dependent STa-stimulated cGMP formation that was undetectable in VVGC-CD853A-infected cells. STa decreased angiotensin II-stimulated human aldosterone generation in a concentration-dependent manner in vaccinia virus-expressing GC-C-infected cells but not in those infected with VVGC-CD853A. These results demonstrate that a catalytically active guanylyl cyclase is required for the inhibition of aldosteronogenesis.

Footnotes

    • Received June 25, 1998.
    • Accepted July 31, 1998.
  • Send reprint requests to: James G. Drewett, Ph.D., Department of Pharmacology and Toxicology, University of North Dakota School of Medicine and Health Sciences, 501 North Columbia Road, Grand Forks, ND 58202-9037. E-mail:drewett{at}badlands.nodak.edu

  • ↵1 Current affiliation: Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226-4801.

  • ↵2 Current affiliation: Department of Pharmacology and Toxicology, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND 58202-9037.

  • This work was supported by National Institutes of Health Grant R29-HL54717 (J.G.D.), American Heart Association, Wisconsin Affiliate, Grant-in-Aid 94-GB-38 (J.G.D.), a National Heart Foundation Research Starter Grant and the 1995 Ruth Salta Junior Investigator Award (both to J.G.D. from the American Health Assistance Foundation), and institutional support from the Medical College of Wisconsin and the University of North Dakota.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 54 (5)
Molecular Pharmacology
Vol. 54, Issue 5
1 Nov 1998
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Research ArticleArticle

Functionally Active Catalytic Domain Is Essential for Guanylyl Cyclase-Linked Receptor Mediated Inhibition of Human Aldosterone Synthesis

Linda J. Olson, Begonia Y. Ho, L. William Cashdollar and James G. Drewett
Molecular Pharmacology November 1, 1998, 54 (5) 761-769; DOI: https://doi.org/10.1124/mol.54.5.761

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Research ArticleArticle

Functionally Active Catalytic Domain Is Essential for Guanylyl Cyclase-Linked Receptor Mediated Inhibition of Human Aldosterone Synthesis

Linda J. Olson, Begonia Y. Ho, L. William Cashdollar and James G. Drewett
Molecular Pharmacology November 1, 1998, 54 (5) 761-769; DOI: https://doi.org/10.1124/mol.54.5.761
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