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Molecular Pharmacology

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Rapid CommunicationAccelerated Communication

Conversion of Forskolin-Insensitive to Forskolin-Sensitive (Mouse-Type IX) Adenylyl Cyclase

Shui-Zhong Yan, Zhi-Hui Huang, Rebecca K. Andrews and Wei-Jen Tang
Molecular Pharmacology February 1998, 53 (2) 182-187; DOI: https://doi.org/10.1124/mol.53.2.182
Shui-Zhong Yan
Department of Pharmacological and Physiological Sciences, University of Chicago, Chicago, Illinois 60637
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Zhi-Hui Huang
Department of Pharmacological and Physiological Sciences, University of Chicago, Chicago, Illinois 60637
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Rebecca K. Andrews
Department of Pharmacological and Physiological Sciences, University of Chicago, Chicago, Illinois 60637
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Wei-Jen Tang
Department of Pharmacological and Physiological Sciences, University of Chicago, Chicago, Illinois 60637
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Abstract

Forskolin potently activates all cloned mammalian adenylyl cyclases except type IX by interacting with two homologous cytoplasmic domains (C1 and C2) that form the catalytic core. A mutational analysis of the IIC2 protein (C2domain from type II adenylyl cyclase) and forskolin analogs suggests that Ser942 interacts with the 7-acetyl group of forskolin. The C1/C2 complex has only one forskolin, one ATP, and one binding site for the α subunit of the G protein that stimulates adenylyl cyclase (Gsα) and its structure may be modeled using the three-dimensional structure of (IIC2/forskolin)2. The Ser942 mutation defines which forskolin in the (IIC2/forskolin)2structure exists in C1/C2 complex. Thus, the forskolin-binding site is close to the Gsα-binding site but distal (15–20Å) from the catalytic site. Mutation from Leu912 of IIC2 protein to tyrosine or alanine severely reduces Gsα activation and completely prevents forskolin activation. The corresponding residue of Leu912 is Tyr1082 at type IX isoform of adenylyl cyclase. Similar to recombinant type IX enzyme, soluble adenylyl cyclase derived from mouse-type IX adenylyl cyclase is sensitive to Gsα activation but not to forskolin. Changing Tyr1082 to leucine makes soluble type IX adenylyl cyclase forskolin-responsive.

Footnotes

    • Received July 17, 1997.
    • Accepted October 29, 1997.
  • Send reprint requests to: Dr. Wei-Jen Tang, Department of Pharmacology & Physiological Science, University of Chicago, MC 0926, 947 East 58th Street, Chicago, IL 60637. E-mail:tang{at}drugs.bsd.uchicago.edu

  • This work was supported by National Institute of Health Grant GM53459, a University of Chicago Cancer Biology Program postdoctoral fellowship (S.-Z.Y.), and Howard Hughes Medical Institute Undergraduate Summer Research fellowship (R.K.A.)

  • S.-Z.Y. and Z.-H.H. contributed equally to this work.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 53 (2)
Molecular Pharmacology
Vol. 53, Issue 2
1 Feb 1998
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Rapid CommunicationAccelerated Communication

Conversion of Forskolin-Insensitive to Forskolin-Sensitive (Mouse-Type IX) Adenylyl Cyclase

Shui-Zhong Yan, Zhi-Hui Huang, Rebecca K. Andrews and Wei-Jen Tang
Molecular Pharmacology February 1, 1998, 53 (2) 182-187; DOI: https://doi.org/10.1124/mol.53.2.182

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Rapid CommunicationAccelerated Communication

Conversion of Forskolin-Insensitive to Forskolin-Sensitive (Mouse-Type IX) Adenylyl Cyclase

Shui-Zhong Yan, Zhi-Hui Huang, Rebecca K. Andrews and Wei-Jen Tang
Molecular Pharmacology February 1, 1998, 53 (2) 182-187; DOI: https://doi.org/10.1124/mol.53.2.182
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