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Molecular Pharmacology

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Research ArticleArticle

Multiple Affinity States of cGMP-Specific Phosphodiesterase for Sildenafil Inhibition Defined by cGMP-Dependent and cGMP-Independent Mechanisms

Irina G. Rybalkina, Xiao-Bo Tang and Sergei D. Rybalkin
Molecular Pharmacology April 2010, 77 (4) 670-677; DOI: https://doi.org/10.1124/mol.109.062299
Irina G. Rybalkina
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Xiao-Bo Tang
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Sergei D. Rybalkin
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Abstract

cGMP-specific phosphodiesterase (PDE5) has become a target for drug development for the treatment of a number of physiological dysfunctions, affected by changes in the cGMP/cGMP-dependent protein kinase (PKG) signaling pathway. PDE5 has two highly homologous regulatory domains, GAF-A and GAF-B. We showed previously that PDE5 could be converted from a low-activity (nonactivated) state to a high-activity state upon cGMP binding to the GAF-A domain with higher sensitivities toward sildenafil (EMBO J 22:469–478, 2003). Here we investigated whether sildenafil sensitivity of PDE5 could be modified by cGMP-independent mechanisms. Individually expressed recombinant GAF-A and GAF-B proteins were tested for their ability to modulate full-length recombinant PDE5 affinity to sildenafil. The GAF-A domain protein had the most dramatic effect on the affinity of the nonactivated recombinant PDE5 for sildenafil, revealing much higher sensitivity to sildenafil inhibition. The apparent affinity for sildenafil increased from the nanomolar range to the picomolar range, providing evidence for the presence of a “super-high” sensitivity state of PDE5 for sildenafil inhibition. In human platelet, higher sensitivity of PDE5 for sildenafil inhibition has been detected after blocking cGMP-binding sites of the GAF-A domain. Thus, our data demonstrate that high sensitivity of PDE5 for sildenafil can be obtained not only through cGMP-induced activation of PDE, but also through cGMP-independent modulation of PDE5 in the nonactivated state, possibly through protein-protein interaction. Furthermore, data suggest that nonactivated PDE5 with “super-high” affinities for sildenafil inhibition may be responsible for therapeutic effects of long-term treatments with low doses of PDE5 inhibitors.

Footnotes

    fn-1
  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • fn-2
  • This work was supported by the American Lung Association [Grant RG-52219N] and the Deutsche Forschungsgemeinschaft [Grant DFG-FOR 923 LU 1490/1-1].

  • fn-3
  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.109.062299.

  • fn-4
  • ABBREVIATIONS:

    PKG
    cGMP-dependent protein kinase
    PDE5
    cGMP-specific phosphodiesterase
    HEK
    human embryonic kidney
    aa
    amino acid
    mAb
    monoclonal antibody
    MOPS
    3-(N-morpholino)propanesulfonic acid
    ED
    erectile dysfunction.

    • Received November 10, 2009.
    • Accepted January 19, 2010.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 77 (4)
Molecular Pharmacology
Vol. 77, Issue 4
1 Apr 2010
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Research ArticleArticle

Multiple Affinity States of cGMP-Specific Phosphodiesterase for Sildenafil Inhibition Defined by cGMP-Dependent and cGMP-Independent Mechanisms

Irina G. Rybalkina, Xiao-Bo Tang and Sergei D. Rybalkin
Molecular Pharmacology April 1, 2010, 77 (4) 670-677; DOI: https://doi.org/10.1124/mol.109.062299

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Research ArticleArticle

Multiple Affinity States of cGMP-Specific Phosphodiesterase for Sildenafil Inhibition Defined by cGMP-Dependent and cGMP-Independent Mechanisms

Irina G. Rybalkina, Xiao-Bo Tang and Sergei D. Rybalkin
Molecular Pharmacology April 1, 2010, 77 (4) 670-677; DOI: https://doi.org/10.1124/mol.109.062299
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