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Research ArticleEndocrine and Diabetes

σ-1 Receptor at the Mitochondrial-Associated Endoplasmic Reticulum Membrane Is Responsible for Mitochondrial Metabolic Regulation

Karla-Sue C. Marriott, Manoj Prasad, Veena Thapliyal and Himangshu S. Bose
Journal of Pharmacology and Experimental Therapeutics December 2012, 343 (3) 578-586; DOI: https://doi.org/10.1124/jpet.112.198168
Karla-Sue C. Marriott
Department of Natural Sciences, College of Science and Technology, Savannah State University, Savannah, Georgia (K.-S.C.M.); and Departments of Biochemistry and Biomedical Sciences, Mercer University School of Medicine and Memorial University Medical Center, Anderson Cancer Institute, Savannah, Georgia (M.P., V.T., H.S.B.)
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Manoj Prasad
Department of Natural Sciences, College of Science and Technology, Savannah State University, Savannah, Georgia (K.-S.C.M.); and Departments of Biochemistry and Biomedical Sciences, Mercer University School of Medicine and Memorial University Medical Center, Anderson Cancer Institute, Savannah, Georgia (M.P., V.T., H.S.B.)
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Veena Thapliyal
Department of Natural Sciences, College of Science and Technology, Savannah State University, Savannah, Georgia (K.-S.C.M.); and Departments of Biochemistry and Biomedical Sciences, Mercer University School of Medicine and Memorial University Medical Center, Anderson Cancer Institute, Savannah, Georgia (M.P., V.T., H.S.B.)
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Himangshu S. Bose
Department of Natural Sciences, College of Science and Technology, Savannah State University, Savannah, Georgia (K.-S.C.M.); and Departments of Biochemistry and Biomedical Sciences, Mercer University School of Medicine and Memorial University Medical Center, Anderson Cancer Institute, Savannah, Georgia (M.P., V.T., H.S.B.)
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Abstract

The mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) is a small section of the outer mitochondrial membrane tethered to the ER by lipid and protein filaments. One such MAM protein is the σ-1 receptor, which contributes to multiple signaling pathways. We found that short interfering RNA-mediated knockdown of σ-1 reduced pregnenolone synthesis by 95% without affecting expression of the inner mitochondrial membrane resident enzyme, 3-β-hydroxysteroid dehydrogenase 2. To explore the underlying mechanism of this effect, we generated a series of σ-receptor ligands: 5,6-dimethoxy-3-methyl-N-phenyl-N-(3-(piperidin-1-yl)propyl)benzofuran-2-carboxamide (KSCM-1), 3-methyl-N-phenyl-N-(3-(piperidin-1-yl)propyl)benzofuran-2-carboxamide (KSCM-5), and 6-methoxy-3-methyl-N-phenyl-N-(3-(piperidin-1-yl) propyl)benzofuran-2-carboxamide (KSCM-11) specifically bound to σ-1 in the nanomolar range, whereas KSCM-5 and KSCM-11 also bound to σ-2. Treatment of cells with the KSCM ligands led to decreased cell viability, with KSCM-5 having the most potent effect followed by KSCM-11. KSCM-1 increased σ-1 expression by 4-fold and progesterone synthesis, whereas the other compounds decreased progesterone synthesis. These differences probably are caused by ligand molecular structure. For example, KSCM-1 has two methoxy substituents at C-5 and C-6 of the benzofuran ring, whereas KSCM-11 has one at C-6. KSCM ligands or σ-1 knockdown did not alter the expression of ER resident enzymes that synthesize steroids. However, coimmunoprecipitation of the σ-1 receptor pulled down voltage-dependent anion channel 2 (VDAC2), whose expression was enhanced by KSCM-1. VDAC2 plays a key role in cholesterol transport into the mitochondria, suggesting that the σ-1 receptor at the MAM coordinates with steroidogenic acute regulatory protein for cholesterol trafficking into the mitochondria for metabolic regulation.

Footnotes

  • K.-S.C.M. and M.P. contributed equally to this work.

  • H.S.B. was supported by the National Institutes of Health [Grant HD057876] and the Anderson Cancer Institute. K.-S.C.M. was supported by the National Institutes of Health National Institute on Drug Abuse [Grant DA027086] and the National Institutes of Health National Center on Minority Health and Health Disparities [Grant 5P20MD003941] (to K.-S.C.M. and H.S.B.).

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

    http://dx.doi.org/10.1124/jpet.112.198168.

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

  • ABBREVIATIONS:

    ER
    endoplasmic reticulum
    MAM
    mitochondria-associated ER membrane
    Ab
    antibody
    IMM
    inner mitochondrial membrane
    IP3
    inositol 1,4,5-triphosphate
    KSCM-1
    5,6-dimethoxy-3-methyl-N-phenyl-N-(3-(piperidin-1-yl)propyl) benzofuran-2-carboxamide
    KSCM-5
    3-methyl-N-phenyl-N-(3-(piperidin-1-yl)propyl)benzofuran-2-carboxamide
    KSCM-11
    6-methoxy-3-methyl-N-phenyl-N-(3-(piperidin-1-yl)propyl) benzofuran-2-carboxamide
    OMM
    outer mitochondrial membrane
    SCC
    side-chain cleavage
    siRNA
    short interfering RNA
    SKF-10047
    2S-[2α,6α,11R*]-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(2-propenyl)-2,6-methano-3-benzazocin-8-ol
    StAR
    steroidogenic acute regulatory protein
    TLC
    thin-layer chromatography
    VDAC
    voltage-dependent anion channel
    3βHSD2
    3-β-hydroxysteroid dehydrogenase.

  • Received July 6, 2012.
  • Accepted August 23, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 343 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 343, Issue 3
1 Dec 2012
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Research ArticleEndocrine and Diabetes

σ-1 Regulates Mitochondrial Enzymatic Activity

Karla-Sue C. Marriott, Manoj Prasad, Veena Thapliyal and Himangshu S. Bose
Journal of Pharmacology and Experimental Therapeutics December 1, 2012, 343 (3) 578-586; DOI: https://doi.org/10.1124/jpet.112.198168

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Research ArticleEndocrine and Diabetes

σ-1 Regulates Mitochondrial Enzymatic Activity

Karla-Sue C. Marriott, Manoj Prasad, Veena Thapliyal and Himangshu S. Bose
Journal of Pharmacology and Experimental Therapeutics December 1, 2012, 343 (3) 578-586; DOI: https://doi.org/10.1124/jpet.112.198168
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