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Horm Metab Res 2012; 44(10): 790-794
DOI: 10.1055/s-0032-1321861
Review
© Georg Thieme Verlag KG Stuttgart · New York

Regulation of Adrenal Steroidogenesis by the High-affinity Phosphodiesterase 8 Family

L-C. L. Tsai
1   Department of Pharmacology, University of Washington, Seattle, Washington, USA
,
J. A. Beavo
1   Department of Pharmacology, University of Washington, Seattle, Washington, USA
› Author Affiliations
Further Information

Publication History

received 30 December 2011

accepted 09 July 2012

Publication Date:
17 August 2012 (online)

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Abstract

The main function of cyclic AMP phosphodiesterases (PDEs) is to degrade cAMP, a ubiquitous second messenger. Therefore, PDEs can function as prime regulators of cAMP/PKA-dependent processes such as steroidogenesis. Until recently, the roles of the PDE8 family have been largely unexplored, presumably due to the lack of a selective inhibitor. This review focuses on recent reports about the regulatory roles of the PDE8 family in adrenal steroidogenesis, as well as the inhibitory properties and specificity of a new PDE8-selective inhibitor, PF-04957325. We also describe a method of measuring urinary corticosterone levels in vivo as a minimally invasive way of monitoring the stress level in a mouse.

Key words

adrenal cortex - glucocorticoids - androgen
 

  • References

  • 1 McCann SM, Antunes-Rodrigues J, Franci CR, Anselmo-Franci JA, Karanth S, Rettori V. Role of the hypothalamic pituitary adrenal axis in the control of the response to stress and infection. Braz J Med Biol Res 2000; 33: 1121-1131
    PubMedSearch in Google Scholar
  • 2 Aguilera G, Kiss A, Liu Y, Kamitakahara A. Negative regulation of corticotropin releasing factor expression and limitation of stress response. Stress 2007; 10: 153-161
    CrossrefPubMedSearch in Google Scholar
  • 3 Macfarlane DP, Forbes S, Walker BR. Glucocorticoids and fatty acid metabolism in humans: fuelling fat redistribution in the metabolic syndrome. J Endocrinol 2008; 197: 189-204
    CrossrefPubMedSearch in Google Scholar
  • 4 Vinson GP. The adrenal cortex and life. Mol Cell Endocrinol 2009; 300: 2-6
    CrossrefPubMedSearch in Google Scholar
  • 5 Vinson GP. Adrenocortical zonation and ACTH. Microsc Res Tech 2003; 61: 227-239
    CrossrefPubMedSearch in Google Scholar
  • 6 Jacobson L. Hypothalamic-pituitary-adrenocortical axis regulation. Endocrinol Metab Clin North Am 2005; 34: 271-292 vii
    CrossrefPubMedSearch in Google Scholar
  • 7 Stocco DM, Wang X, Jo Y, Manna PR. Multiple signaling pathways regulating steroidogenesis and steroidogenic acute regulatory protein expression: more complicated than we thought. Mol Endocrinol 2005; 19: 2647-2659
    Search in Google Scholar
  • 8 Manna PR, Dyson MT, Stocco DM. Regulation of the steroidogenic acute regulatory protein gene expression: present and future perspectives. Mol Hum Reprod 2009; 15: 321-333
    CrossrefPubMedSearch in Google Scholar
  • 9 Stocco DM. Tracking the role of a star in the sky of the new millennium. Mol Endocrinol 2001; 15: 1245-1254
    CrossrefPubMedSearch in Google Scholar
  • 10 Cherradi N, Pardo B, Greenberg AS, Kraemer FB, Capponi AM. Angiotensin II activates cholesterol ester hydrolase in bovine adrenal glomerulosa cells through phosphorylation mediated by p42/p44 mitogen-activated protein kinase. Endocrinology 2003; 144: 4905-4915
    CrossrefPubMedSearch in Google Scholar
  • 11 Lucki NC, Li D, Sewer MB. Sphingosine-1-phosphate rapidly increases cortisol biosynthesis and the expression of genes involved in cholesterol uptake and transport in H295R adrenocortical cells. Mol Cell Endocrinol 2012; 348: 165-175
    CrossrefPubMedSearch in Google Scholar
  • 12 Davis IJ, Lau LF. Endocrine and neurogenic regulation of the orphan nuclear receptors Nur77 and Nurr-1 in the adrenal glands. Mol Cell Biol 1994; 14: 3469-3483
    PubMedSearch in Google Scholar
  • 13 Simpson ER, Waterman MR. Regulation of the synthesis of steroidogenic enzymes in adrenal cortical cells by ACTH. Annu Rev Physiol 1988; 50: 427-440
    Search in Google Scholar
  • 14 Sewer MB, Waterman MR. ACTH modulation of transcription factors responsible for steroid hydroxylase gene expression in the adrenal cortex. Microsc Res Tech 2003; 61: 300-307
    CrossrefPubMedSearch in Google Scholar
  • 15 Sewer MB, Dammer EB, Jagarlapudi S. Transcriptional regulation of adrenocortical steroidogenic gene expression. Drug Metab Rev 2007; 39: 371-388
    Search in Google Scholar
  • 16 Hammer GD, Parker KL, Schimmer BP. Minireview: transcriptional regulation of adrenocortical development. Endocrinology 2005; 146: 1018-1024
    PubMedSearch in Google Scholar
  • 17 Conti M, Beavo J. Biochemistry and physiology of cyclic nucleotide phosphodiesterases: essential components in cyclic nucleotide signaling. Annu Rev Biochem 2007; 76: 481-511
    Search in Google Scholar
  • 18 Soderling SH, Bayuga SJ, Beavo JA. Identification and characterization of a novel family of cyclic nucleotide phosphodiesterases. J Biol Chem 1998; 273: 15553-15558
    CrossrefPubMedSearch in Google Scholar
  • 19 Fisher DA, Smith JF, Pillar JS, St Denis SH, Cheng JB. Isolation and characterization of PDE8A, a novel human cAMP-specific phosphodiesterase. Biochem Biophys Res Commun 1998; 246: 570-577
    CrossrefPubMedSearch in Google Scholar
  • 20 Soderling SH, Bayuga SJ, Beavo JA. Cloning and characterization of a cAMP specific cyclic nucleotide phosphodiesterase. Proc Natl Acad Sci USA 1998; 95: 8991-8996
    CrossrefPubMedSearch in Google Scholar
  • 21 Wang P, Wu P, Egan RW, Billah MM. Human phosphodiesterase 8A splice variants: cloning, gene organization, and tissue distribution. Gene 2001; 280: 183-194
    CrossrefPubMedSearch in Google Scholar
  • 22 Hayashi M, Matsushima K, Ohashi H, Tsunoda H, Murase S, Kawarada Y, Tanaka T. Molecular cloning and characterization of human PDE8B, a novel thyroid-specific isozyme of 3′,5′-cyclic nucleotide phosphodiesterase. Biochem Biophys Res Commun 1998; 250: 751-756
    CrossrefPubMedSearch in Google Scholar
  • 23 Lakics V, Karran EH, Boess FG. Quantitative comparison of phosphodiesterase mRNA distribution in human brain and peripheral tissues. Neuropharmacology 2010; 59: 367-374
    CrossrefPubMedSearch in Google Scholar
  • 24 Horvath A, Giatzakis C, Tsang K, Greene E, Osorio P, Boikos S, Libe R, Patronas Y, Robinson-White A, Remmers E, bertherat J, Nesterova M, Stratakis CA. A cAMP specific phosphodiesterase (PDE8B) that is mutated in adrenal hyperplasia is expressed widely in human and mouse tissues: a novel PDE8B isoform in human adrenal cortex. Eur J Hum Genet 2008; 16: 1245-1253
    CrossrefPubMedSearch in Google Scholar
  • 25 Kobayashi T, Gamanuma M, Sasaki T, Yamashita Y, Yuasa K, Kotera J, Omori K. Molecular comparison of rat cyclic nucleotide phosphodiesterase 8 family: unique expression of PDE8B in rat brain. Gene 2003; 319: 21-31
    CrossrefPubMedSearch in Google Scholar
  • 26 Shimizu-Albergine M, Tsai LC, Patrucco E, Beavo JA. cAMP-specific phosphodiesterases 8A and 8B, essential regulators of Leydig cell steroidogenesis. Mol Pharmacol 2012; 81: 556-566
    CrossrefPubMedSearch in Google Scholar
  • 27 Tsai LC, Shimizu-Albergine M, Beavo JA. The high-affinity cAMP-specific phosphodiesterase 8B controls steroidogenesis in the mouse adrenal gland. Mol Pharmacol 2011; 79: 639-648
    CrossrefPubMedSearch in Google Scholar
  • 28 DeNinno MP, Wright SW, Visser MS, Etienne JB, Moore DE, Olson TV, Rocke BN, Andrews MP, Zarbo C, Millham ML, Boscoe BP, Boyer BD, Doran SD, Houseknecht KL. 1,5-Substituted nipecotic amides: selective PDE8 inhibitors displaying diastereomer dependent microsomal stability. Bioorg Med Chem Lett 2011; 21: 3095-3098
    CrossrefPubMedSearch in Google Scholar
  • 29 Vang AG, Ben-Sasson SZ, Dong H, Kream B, DeNinno MP, Claffey MM, Housley W, Clark RB, Epstein PM, Brocke S. PDE8 regulates rapid Teff cell adhesion and proliferation independent of ICER. PLoS One 2010; 5: e12011
    CrossrefPubMedSearch in Google Scholar
  • 30 Dong H, Osmanova V, Epstein PM, Brocke S. Phosphodiesterase 8 (PDE8) regulates chemotaxis of activated lymphocytes. Biochem Biophys Res Commun 2006; 345: 713-719
    CrossrefPubMedSearch in Google Scholar
  • 31 Vasta V, Shimizu-Albergine M, Beavo JA. Modulation of Leydig cell function by cyclic nucleotide phosphodiesterase 8A. Proc Natl Acad Sci USA 2006; 103: 19925-19930
    CrossrefPubMedSearch in Google Scholar
  • 32 Shimizu-Albergine M, Tsai LCL, Beavo JA. cAMP-specific phosphodiesterases 8A and 8B, essential regulators of Leydig cell steroidogenesis. Mol Pharmacol Jan 2012; [Epub ahead of print]
    PubMedSearch in Google Scholar
  • 33 Chen C, Wickenheisser J, Ewens KG, Ankener W, Legro RS, Dunaif A, McAllister JM, Spielman RS, Strauss 3rd JF. PDE8A genetic variation, polycystic ovary syndrome and androgen levels in women. Mol Hum Reprod 2009; 15: 459-469
    CrossrefPubMedSearch in Google Scholar
  • 34 Patrucco E, Albergine MS, Santana LF, Beavo JA. Phosphodiesterase 8A (PDE8A) Regulates Excitation-Contraction Coupling in Ventricular Myocytes. J Mol Cell Cardiol 2010; 49: 330-333
    CrossrefPubMedSearch in Google Scholar
  • 35 Arnaud-Lopez L, Usala G, Ceresini G, Mitchell BD, Pilia MG, Piras MG, Sestu N, Maschio A, Busonero F, Albai G, Dei M, Lai S, Mulas A, Crisponi L, Tanaka T, Bandinelli S, Guralnik JM, Loi A, Balaci L, Sole G, Prinzis A, Mariotti S, Shuldiner AR, Cao A, Schlessinger D, Uda M, Abecasis GR, Nagaraja R, Sanna S, Naitza S. Phosphodiesterase 8B gene variants are associated with serum TSH levels and thyroid function. Am J Hum Genet 2008; 82: 1270-1280
    CrossrefPubMedSearch in Google Scholar
  • 36 Appenzeller S, Schirmacher A, Halfter H, Baumer S, Pendziwiat M, Timmerman V, De Jonghe P, Fekete K, Stogbauer F, Ludemann P, Hund M, Quabius ES, Ringelstein EB, Kuhlenbaumer G. Autosomal-dominant striatal degeneration is caused by a mutation in the phosphodiesterase 8B gene. Am J Hum Genet 2010; 86: 83-87
    CrossrefPubMedSearch in Google Scholar
  • 37 Dov A, Abramovitch E, Warwar N, Nesher R. Diminished phosphodiesterase-8B potentiates biphasic insulin response to glucose. Endocrinology 2008; 149: 741-748
    PubMedSearch in Google Scholar
  • 38 Meijer MK, Lemmens AG, Van Zutphen BF, Baumans V. Urinary corticosterone levels in mice in response to intraperitoneal injections with saline. J Appl Anim Welf Sci 2005; 8: 279-283
    CrossrefPubMedSearch in Google Scholar