Abstract
It has been suggested that corticotropin-releasing hormone (CRH) receptors CRH-R1 and CRH-R2 might be involved in the modulation of uterine activity during pregnancy. The authors determine the localization, concentrations, and variants of CRH-R1 and CRH-R2 in the human pregnant myometrium from patients undergoing labor and patients not undergoing labor. Biopsies were taken from 40 patients undergoing either elective or emergency cesarean delivery after spontaneous labor. The localization of CRH-R1 and CRH-R2 was examined by immunohistochemistry. The mRNA and protein levels of CRH-R1 and CRH-R2 were measured by quantitative reverse-transcriptase polymerase chain reaction (PCR) and Western blot analysis, respectively. The variants of CRH-R1 and CRH-R2 were determined by PCR analysis followed by sequencing. Both CRH-R1 and CRH-R2 were found by immunohistochemistry to be expressed by smooth muscle cells in the pregnant myometrium. There was no significant difference in mRNA and protein levels of CRH-R1 and CRH-R2 in myometria between the labor and nonlabor groups. Levels of CRH-R1 α, R1 β, R1c, R1e, R1f, and R2 α were identified in the pregnant myometrium, and levels of CRH-R1 α, R1c, and R2 α were detected in both the term labor and nonlabor myometrium. A heterogeneous distribution of other CRH-R1 variants in term labor and nonlabor myometrium was observed. Human myometrium expresses both CRH-R1 and CRH-R2 during pregnancy. A heterogeneous distribution of CRH-R1 variants in term labor and nonlabor myometrium might be related to the effects of CRH on contractile phenotype of myometrium at the term.
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References
Lenz HJ, Raedler A., Greten H., Brown MR CRF initiates biological action within the brain that are observed in response to stress. Am J Physiol. 1987;21:34–39.
Chrousos G., Gold P. The concepts of stress and stress system disorders. JAMA. 1992;267:1244–1252.
Suda T., Tomori N., Tozawa F., Mouri T., Demura H., Shizume K. Distribution and characterization of immunoreactive corticotropin-releasing factor in human tissue. J Clin Endocrinol Metab. 1984;55:861–866.
Shibasai T., Oagirl Ehizume K, Ling N. Corticotropin-releasing factor-like activity in human extracts. J Clin Endocrinol Metab. 1982;55:384–386.
Usui T., Nakai Y., Tsukada T., et al. Expression of adrenocorticotropin-releasing hormone precursor gene in placenta and other nonhypothalamic tissues in man. Mol Endocrinol. 1988;2:871–875.
De Souza EB Corticotropin-releasing factor receptors: physiology, pharmacology, biochemistry and role in central nervous system and immune disorders. Psychoneuroendocrinology. 1995;20:789–818.
Owens MJ, Nemeroff CB Physiology and pharmacology of corticotropin-releasing factor. Pharmacol Rev. 1991;43:425–473.
McLean M., Bistis A., Davies JJ, Woods R., Lowry PJ, Smith R. A placental clock controlling the length of human pregnancy. Nat Med. 1995;1:460–463.
Chen R., Lewis KA, Perrin MH, Vale WW Expression cloning of a human corticotropin-releasing-factor receptor. Proc Natl Acad Sci U S A. 1993;90:8967–8971.
Liaw CW, Lovenberg TW, Barry G., Oltersdorf T., Grigoriadis DE, De Souza EB. Cloning and characterization of the human corticotropin-releasing factor-2 receptor complementary deoxyribonucleic acid. Endocrinology. 1996;137:72–77.
Pisarchik A., Slominski AT Alternative splicing of CRH-R1 receptors in human and mouse skin: identification of new variants and their differential expression. FASEB J. 2001;15:2754–2756.
Valdenaire O., Giller T., Breu V., Gottowik J., Kilpatrick G. A new functional isoform of the human CRF2 receptor for corticotropin-releasing factor. Biochim Biophys Acta. 1997;1352:129–132.
Kostich WA, Chen A., Sperle K., Largent BL Molecular identification and analysis of a novel human corticotropin-releasing factor (CRF) receptor: the CRF2γ receptor. Mol Endocrinol. 1998;12:1077–1085.
Vaughan J., Donaldson C., Bittencourt J., et al. Urocortin, a mammalian neuropeptide related to fish urotensin I and to corticotrophin-releasing factor. Nature. 1996;378:287–292.
Hsu SY, Hsueh AJ Human stresscopin and stresscopin-related peptide are selective ligands for the type 2 corticotropin-releasing hormone receptor. Nat Med. 2001;7:605–611.
Lewis K., Li C., Perrin MH, et al. Identification of urocortin III, an additional member of the corticotropin-releasing factor (CRF) family with high affinity for the CRF2 receptor. Proc Natl Acad Sci U S A. 2001;98:7570–7575.
Dautzenberg FM, Py-Lang G., Higelin J., Fischer C., Wright MB, Huber G. Different binding modes of amphibian and human corticotropin-releasing factor type 1 and type 2 receptors: evidence for evolutionary differences. J Pharmacol Exp Ther. 2001;296:113–120.
Sehringer B., Zahradnik HP, Simon M., Ziegler R., Noethling C., Schaefer WR mRNA expression profiles for corticotrophin-releasing hormone, urocortin, CRH-binding protein and CRH receptors in human term gestational tissues determined by real-time quantitative RT-PCR. J Mol Endocrinol. 2004; 32:339–348.
Imperatore A., Florio P., Torres PB, et al. Urocortin 2 and urocortin 3 are expressed by the human placenta, deciduas, and fetal membranes. Am J Obstet Gynecol. 2006;195:288–295.
Karteris E., Hillhous EW, Grammatopoulos DK Urocortin II is expressed in human pregnant myometrial cells and regulates myosin light chain phosphorylation: potential role of the type-2 conticotropin-releasing hormone receptor in the control of myometrial contractility. Endocrinology. 2004;145:890–900.
Sasaki A., Shinkawa O., Margioris AN, et al. Immunoreactive corticotropin-releasing hormone in human plasma during pregnancy, labor and delivery. J Clin Endocrinol Metab. 1987; 64:224–229.
Warren WB, Patrick SL, Goland RS Elevated maternal plasma corticotropin-releasing hormone levels in pregnancies complicated by preterm labor. Am J Obstet Gynecol. 1992;166:1198–1204.
Grammatopoulos D., Dai Y., Chen J., et al. Human corticotropin-releasing hormone receptor: difference in subtype expression between pregnant and nonpregnant myometria. J Clin Endocrinol Metab. 1998;83:2539–2544.
Rodriguez-Linares B., Linton EA, Phaneuf S. Expression of corticotrophin-releasing hormone receptor mRNA and protein in the human myometrium. J Endocrinol. 1998;156:15–21.
Wetzka B., Sehringer B., Schäfer WR, et al. Expression patterns of CRH, CRH receptors, and CRH binding protein in human gestational tissue at term. Exp Clin Endocrinol Diabetes. 2003;111:154–161.
Aggelidou E., Hillhouse EW, Grammatopoulos D. Up-regulation of nitric oxide synthase and modulation of the guanylate cyclase activity by corticotrophin-releasing hormone but not urocortin II or urocortin III in cultured human pregnant myometrial cells. Proc Natl Acad Sci U S A. 2002;99:3300–3305.
Hillhouse EW, Grammatopoulos D. Control of intracellular signaling by corticotropin-releasing hormone in human myometrium. Front Horm Res. 2001;27:66–74.
Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987;162:156–159.
Kateris E., Papadopoulou N., Grammatopoulos DK, Hillhouse EW Expression and signaling characteristics of the corticotrophin-releasing hormone receptors during the implantation phase in the human endometrium. J Mol Endocrinol. 2004;32:21–32.
Livak KJ, Schmittgen TD Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 2001;25:402–408.
Pisarchik A., Slominski A. Molecular and functional characterization of novel CRFR1 isoforms from the skin. Eur J Biochem. 2004;271:2821–2830.
Stevens MY, Challis Jrg, Lye SJ Corticotropin-releasing hormone receptor subtype 1 is significantly up-regulated at the time of labor in the human myometrium. J Clin Endocrinol Metab. 1998;83:4107–4115.
Grammatopoulos D., Dai Y., Randeva HS, et al. A novel spliced variant of the type 1 corticotropin-releasing hormone receptor with a deletion in the seventh transmembrane domain present in the human pregnant term myometrium and fetal membranes. Mol Endocrinol. 1999;13:2189–2202.
Sirianni R., Mayhew BA, Carr BR, Parker CR, Rainey WE Corticotropin-releasing hormone (CRH) and urocortin act through type 1 CRH receptors to stimulate dehydroepiandrosterone sulfate production in human fetal adrenal cells. J Clin Endocrinol Metab. 2005;90:5393–5400.
Karteris E., Goumenou A., Koumantakis E., Hillhouse EW, Grammatopoulos DK Reduced expression of corticotropin-releasing hormone receptor type-1α in human preeclamptic and growth-restricted placentas. J Clin Endocrinol Metab. 2003;88:363–370.
Grammatopoulos DK, Randeva HS, Levine MA, Katsanou ES, Hillhouse EW Urocortin, but not corticotropin-releasing hormone (CRH), activates the mitogen-activated protein kinase signal transduction pathway in human pregnant myometrium: an effect mediated via R1alpha and R2beta CRH receptor subtypes and stimulation of Gq-proteins. Mol Endocrinol. 2000;14:2076–2091.
Wille S., Sydow S., Palchaudhuri MR, Spiess J., Dautzenberg FM Identification of amino acids in the N-terminal domain of corticotropin-releasing factor receptor 1 that are important determinants of high-affinity ligand binding. J Neurochem. 1999;72:388–395.
Hillhouse EW, Grammatopoulos DK The molecular mechanisms underlying the regulation of the biological activity of corticotropin-releasing hormone receptors: implications for physiology and pathophysiology. Endocr Rev. 2006;27:260–286.
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This work is supported by the Natural Science Foundation of China (30170982 and. 30571961).
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Jin, D., He, P., You, X. et al. Expression of Corticotropin-Releasing Hormone Receptor Type 1 and Type 2 in Human Pregnant Myometrium. Reprod. Sci. 14, 568–577 (2007). https://doi.org/10.1177/1933719107307821
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DOI: https://doi.org/10.1177/1933719107307821