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Molecular Pharmacology

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Research ArticleArticle

cAMP-Specific Phosphodiesterases 8A and 8B, Essential Regulators of Leydig Cell Steroidogenesis

Masami Shimizu-Albergine, Li-Chun Lisa Tsai, Enrico Patrucco and Joseph A. Beavo
Molecular Pharmacology April 2012, 81 (4) 556-566; DOI: https://doi.org/10.1124/mol.111.076125
Masami Shimizu-Albergine
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Li-Chun Lisa Tsai
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Enrico Patrucco
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Joseph A. Beavo
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Abstract

Phosphodiesterase (PDE) 8A and PDE8B are high-affinity, cAMP-specific phosphodiesterases that are highly expressed in Leydig cells. PDE8A is largely associated with mitochondria, whereas PDE8B is broadly distributed in the cytosol. We used a new, PDE8-selective inhibitor, PF-04957325, and genetically ablated PDE8A(−/−), PDE8B(−/−) and PDE8A(−/−)/B(−/−) mice to determine roles for these PDEs in the regulation of testosterone production. PF-04957325 treatment of WT Leydig cells or MA10 cells increased steroid production but had no effect in PDE8A (−/−)/B(−/−) double-knockout cells, confirming the selectivity of the drug. Moreover, under basal conditions, cotreatment with PF-04957325 plus rolipram, a PDE4-selective inhibitor, synergistically potentiated steroid production. These results suggest that the pool(s) of cAMP regulating androgen production are controlled by PDE8s working in conjunction with PDE4. Likewise, PDE8A (−/−)/B(−/−) cells had higher testosterone production than cells from either PDE8A(−/−) or PDE8B(−/−) mice, suggesting that both PDE8s work in concert to regulate steroid production. We further demonstrate that combined inhibition of PDE8s and PDE4 greatly increased PKA activity including phosphorylation of cholesterol-ester hydrolase (CEH)/hormone-sensitive lipase (HSL). CEH/HSL phosphorylation also was increased in PDE8A(−/−)/B(−/−) cells compared with WT cells. Finally, combined inhibition of PDE8s and PDE4 increased the expression of steroidogenic acute regulatory (StAR) protein. Together these findings suggest that both PDE8A and PDE8B play essential roles to maintain low cAMP levels, thereby suppressing resting steroidogenesis by keeping CEH/HSL inactive and StAR protein expression low. They also suggest that in order for PDE inhibitor therapy to be an effective stimulator of steroidogenesis, both PDE8 isozymes and PDE4 need to be simultaneously targeted.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant R01-GM083926] (to J.A.B.), [Grant R01-GM083926-02S1] (an American Recovery and Reinvestment Act of 2009 Supplement).

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

    http://dx.doi.org/10.1124/mol.111.076125.

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

  • ABBREVIATIONS:

    PKA
    cAMP-dependent protein kinase
    PDE
    phosphodiesterase
    LH
    luteinizing hormone
    CEH
    cholesterol ester hydrolase
    HSL
    hormone-sensitive lipase
    StAR
    steroidogenic acute regulatory
    IBMX
    3-isobutyl-1-methylxanthine
    WT
    wild type
    BSA
    bovine serum albumin
    3β-HSD
    3β-hydroxysteroid dehydrogenase
    PBS
    phosphate-buffered saline
    ELISA
    enzyme-linked immunosorbent assay
    PFA
    paraformaldehyde
    Bay 60-7550
    2-(3,4-dimethoxybenzyl)-7-((1R)-1-((1R)-1-hydroxyethyl)- 4-phenylbutyl)-5-methyl imidazo(5,1-f)(1,2,4)triazin-4 (3H)-one
    MOPS
    3-(N-morpholino)propanesulfonic acid
    GFP
    green fluorescent protein
    shRNA
    short hairpin RNA
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase.

  • Received September 28, 2011.
  • Accepted January 5, 2012.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 81 (4)
Molecular Pharmacology
Vol. 81, Issue 4
1 Apr 2012
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Research ArticleArticle

PDE8s in Leydig Cell Steroidogenesis

Masami Shimizu-Albergine, Li-Chun Lisa Tsai, Enrico Patrucco and Joseph A. Beavo
Molecular Pharmacology April 1, 2012, 81 (4) 556-566; DOI: https://doi.org/10.1124/mol.111.076125

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Research ArticleArticle

PDE8s in Leydig Cell Steroidogenesis

Masami Shimizu-Albergine, Li-Chun Lisa Tsai, Enrico Patrucco and Joseph A. Beavo
Molecular Pharmacology April 1, 2012, 81 (4) 556-566; DOI: https://doi.org/10.1124/mol.111.076125
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