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Molecular Pharmacology

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Research ArticleArticle

Alteration in Accumulated Aldosterone Synthesis As a Result of N-Terminal Cleavage of Aldosterone Synthase

Brian P. Adams and Himangshu S. Bose
Molecular Pharmacology March 2012, 81 (3) 465-474; DOI: https://doi.org/10.1124/mol.111.076471
Brian P. Adams
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Himangshu S. Bose
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Abstract

Aldosterone synthase (AS) regulates blood volume by synthesizing the mineralocorticoid aldosterone. Overproduction of aldosterone in the adrenal gland can lead to hypertension, a major cause of heart disease and stroke. Aldosterone production depends upon stimulation of AS expression by the renin-angiotensin system, which takes 12 h to reach full effect, and then 24 h to subside. However, this promoter-dependent regulation of aldosterone production fails to explain phenomena such as rapid-onset hypertension that occurs quickly and then subsides. Here, we investigate the fate of AS after expression and how these events relate to aldosterone production. Using isolated mitochondria from steroidogenic cells and cell-free synthesized AS, we first showed that the precursor form of AS translocated into the matrix of the mitochondria, where it underwent cleavage by mitochondrial processing peptidase to a mature form approximately 54 kDa in size. Mature AS seemed to translocate across the inner mitochondrial membrane a second time to finally reside in the intermembrane space. Unprocessed N-terminal AS has 2-fold more activity than physiological levels. These results show how the subcellular mechanisms of AS localization relate to production of aldosterone and reveal a rapid, promoter-independent regulation of aldosterone production.

Footnotes

  • This work was supported by the National Institutes of Health [Grant HD057876] and the Anderson Cancer Institute (H.S.B.).

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

    http://dx.doi.org/10.1124/mol.111.076471.

  • ABBREVIATIONS:

    AS
    aldosterone synthase
    DOC
    deoxycorticosterone
    SCC
    cytochrome P450 side-chain cleavage enzyme
    ANGII
    angiotensin II
    MPP
    mitochondrial processing peptidase
    IMS
    intermembrane space
    CFS
    cell-free transcription/translation
    RIA
    radioimmunoassay
    OMM
    outer mitochondrial membrane
    MPP
    mitochondrial processing peptidase
    IMM
    inner mitochondrial membrane
    COXIV
    cytochrome c oxidase subunit IV
    DHFR
    dihydrofolate reductase
    Hsp70
    heat shock protein 70
    Tim
    translocase inner membrane
    Tom
    translocase outer membrane.

  • Received October 19, 2011.
  • Accepted December 19, 2011.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 81 (3)
Molecular Pharmacology
Vol. 81, Issue 3
1 Mar 2012
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Research ArticleArticle

AS Regulates Aldosterone Production in Mitochondria

Brian P. Adams and Himangshu S. Bose
Molecular Pharmacology March 1, 2012, 81 (3) 465-474; DOI: https://doi.org/10.1124/mol.111.076471

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Research ArticleArticle

AS Regulates Aldosterone Production in Mitochondria

Brian P. Adams and Himangshu S. Bose
Molecular Pharmacology March 1, 2012, 81 (3) 465-474; DOI: https://doi.org/10.1124/mol.111.076471
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