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Research ArticleCELLULAR AND MOLECULAR

Agonist-Specific Compartmentation of cGMP Action in Myometrium

Iain L. O. Buxton, Deanna Milton, Scott D. Barnett and Stephen D. Tichenor
Journal of Pharmacology and Experimental Therapeutics October 2010, 335 (1) 256-263; DOI: https://doi.org/10.1124/jpet.110.171934
Iain L. O. Buxton
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Deanna Milton
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Scott D. Barnett
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Stephen D. Tichenor
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Abstract

Nitric oxide relaxes myometrium in a cGMP-independent manner. Although cGMP activates its cognate kinase, this is not required for the inhibitory effect of nitric oxide. Thus, nitric oxide-mediated cGMP elevation does not enjoy the same set of substrates as it does in other smooth muscles. To further understand the regulation of relaxation of uterine muscle by cGMP, we have studied the actions of peptide-mediated cGMP action in guinea pig myometrium. We used both functional and biochemical studies of the action of the particulate guanylyl cyclase activator uroguanylin and its receptor, particulate guanylyl cyclase type C, to address the relationship between cGMP elevation acting in the membrane signaling domain to that of the nonmembrane region of the cell. Uroguanylin relaxed oxytocin-induced contractions in a dose-dependent fashion only in pregnant myometrium. Both relaxation and cGMP accumulation after uroguanylin stimulation were blocked by the putative particulate guanylyl cyclase type C inhibitors 2-chloro-ATP and isatin (1H-indole-2,3-dione), but not by the soluble guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-A]quinoxalin-1-one (ODQ). Uroguanylin stimulated cGMP accumulation only in the pregnant myometrium. Caveolin-1 expression increased in pregnancy toward term. In the caveolin-1-containing membrane domain, uroguanylin, but not the nitric-oxide donor, led to the elevation of cGMP that was insensitive to ODQ. Particulate guanylyl cyclase C was expressed and prouroguanylin was detected in pregnant myometrium. We conclude that a uroguanylin–particulate cyclase-cGMP relaxation pathway is present and cGMP is compartmented in myometrium. The agonist-mediated selectivity of relaxation to cGMP is of fundamental pharmacological interest in understanding signal transduction in smooth muscle.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of Child Health and Human Development [Grant HD053028] and a Prematurity Research Initiative Grant from the March of Dimes.

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

    doi:10.1124/jpet.110.171934.

  • ABBREVIATIONS:

    NO
    nitric oxide
    PKG
    cGMP-dependent protein kinase
    sGC
    soluble guanylyl cyclase
    pGC
    particulate guanylyl cyclase
    pGC-C
    pGC type C
    uGN
    uroguanylin
    DIGs
    detergent-insoluble glycolipid-rich membrane fraction
    SNAP
    S-nitroso-N-acetylpenicillamine
    ODQ
    1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one
    isatin
    1H-indole-2,3-dione
    2Cl-ATP
    2-chloro-ATP
    bp
    base pairs
    RT-PCT
    reverse transcription-polymerase chain reaction
    FTU
    full thickness uterus
    MYO
    myometrium
    DEC
    decidua
    INT
    intestine
    DUOD
    duodenum
    GAPDH
    glyceraldehyde-3-phosphate dehydrogenase
    GI
    gastrointestinal
    OT
    oxytocin
    AEBSF
    4-(2-aminoethyl) benzenesulphonyl fluoride hydrochloride
    PBS
    phosphate-buffered saline
    MES
    4-morpholineethanesulfonic acid
    NP
    nonpregnant.

  • Received June 23, 2010.
  • Accepted July 21, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 381 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 381, Issue 2
1 May 2022
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Research ArticleCELLULAR AND MOLECULAR

Agonist-Specific Compartmentation of cGMP Action in Myometrium

Iain L. O. Buxton, Deanna Milton, Scott D. Barnett and Stephen D. Tichenor
Journal of Pharmacology and Experimental Therapeutics October 1, 2010, 335 (1) 256-263; DOI: https://doi.org/10.1124/jpet.110.171934

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Research ArticleCELLULAR AND MOLECULAR

Agonist-Specific Compartmentation of cGMP Action in Myometrium

Iain L. O. Buxton, Deanna Milton, Scott D. Barnett and Stephen D. Tichenor
Journal of Pharmacology and Experimental Therapeutics October 1, 2010, 335 (1) 256-263; DOI: https://doi.org/10.1124/jpet.110.171934
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