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Research ArticleArticle

Activating Mutation of Adenylyl Cyclase Reverses its Inhibition by G Proteins

Gregor Zimmermann, Dongmei Zhou and Ronald Taussig
Molecular Pharmacology November 1999, 56 (5) 895-901; DOI: https://doi.org/10.1124/mol.56.5.895
Gregor Zimmermann
Department of Biological Chemistry, The University of Michigan Medical School, Ann Arbor, Michigan
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Dongmei Zhou
Department of Biological Chemistry, The University of Michigan Medical School, Ann Arbor, Michigan
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Ronald Taussig
Department of Biological Chemistry, The University of Michigan Medical School, Ann Arbor, Michigan
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Abstract

We have implemented a yeast genetic selection developed previously by our laboratory to identify mutant mammalian type V adenylyl cyclases insensitive to inhibition by Gi α .One mutation isolated was localized to the first cytoplasmic domain at a Phe residue (position 400), which is conserved in all nine isoforms of membrane-bound mammalian adenylyl cyclase. Biochemical characterization of the F400Y mutant revealed a dramatic conversion of the Gi α response from inhibitory to stimulatory. This mutation results in additional activating effects. The mutant exhibits an enhanced sensitivity toward activation by either Gs α or forskolin. Synergism between Gs α and forskolin is not observed for the F400Y mutant, presumably because the mutant already is in the sensitized state. Additionally, an enhancement of the basal unstimulated activity was observed. This mutation, which is the first demonstration of an activating point in a mammalian adenylyl cyclase, mimics a sensitized conformation of the wild-type enzyme that underlies the synergism between stimulatory inputs, and additionally, removes the inhibitory regulatory input provided by Gi α. Because sensitizing adenylyl cyclase toward its stimulators can have profound biological implications, this raises the possibility that naturally occurring mutations resembling those at the Phe400 residue may be associated with human disease states.

Footnotes

    • Received June 18, 1999.
    • Accepted August 16, 1999.
  • Send reprint requests to: Dr. Ronald Taussig, Department of Biological Chemistry, The University of Michigan Medical School, Ann Arbor, MI 48109-0636. E-mail:taussig{at}umich.edu

  • This work was supported by United States Public Health Service Grant (GM53645) and the Burroughs Wellcome Foundation.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 56 (5)
Molecular Pharmacology
Vol. 56, Issue 5
1 Nov 1999
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Research ArticleArticle

Activating Mutation of Adenylyl Cyclase Reverses its Inhibition by G Proteins

Gregor Zimmermann, Dongmei Zhou and Ronald Taussig
Molecular Pharmacology November 1, 1999, 56 (5) 895-901; DOI: https://doi.org/10.1124/mol.56.5.895

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Research ArticleArticle

Activating Mutation of Adenylyl Cyclase Reverses its Inhibition by G Proteins

Gregor Zimmermann, Dongmei Zhou and Ronald Taussig
Molecular Pharmacology November 1, 1999, 56 (5) 895-901; DOI: https://doi.org/10.1124/mol.56.5.895
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