Evidence map›Paper›PMID 22232524›Full record

ArticleMolecular pharmacology2012

cAMP-specific phosphodiesterases 8A and 8B, essential regulators of Leydig cell steroidogenesis.

Masami Shimizu-Albergine, Li-Chun Lisa Tsai, Enrico Patrucco, Joseph A Beavo

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular pharmacology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.

0numbers the graph read from it
0cells of the map it votes in
43citing papers in PubMed
2.1field-weighted citation impact, top 12% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

43 citing papers in PubMed, 77 citations in OpenAlex.

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  12. Plasticity and therapeutic potential of cAMP and cGMP-specific phosphodiesterases inComputational and structural biotechnology journal · 2022
    Article
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  20. The protozoan parasiteComputational and structural biotechnology journal · 2020
    Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

4 authors at 2 institutions in 2 countries.

Masami Shimizu-AlbergineDepartment of Pharmacology, University of Washington, Seattle, Washington 98195-7280, USA.
Li-Chun Lisa Tsai
Enrico Patrucco
Joseph A Beavo
University of Washington · USTechnical University of Munich · DE

Funding

Regulation of Cellular Functions by Cyclic Nucleotide Phosphodiesterase 8R01GM083926 · NIGMS · UNIVERSITY OF WASHINGTON · PI BEAVO, JOSEPH A · 2008 to 2015
$3.0M
NIGMS NIH HHS R01 GM083926NIGMS NIH HHS R01-GM083926NIGMS NIH HHS R01-GM083926-02S1
6 · The paper itself

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.

Indexed as

3',5'-Cyclic-AMP PhosphodiesterasesAnimalsImmunoprecipitationIsoenzymesLeydig CellsMaleMiceMice, KnockoutSteroids3',5'-Cyclic-AMP PhosphodiesterasesIsoenzymesSteroids

Identifiers

PMID22232524
PMCPMC3310417
OpenAlexW2105996457

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.