Tachykinin Receptor and Neutral Endopeptidase Gene Expression in the Rat Uterus: Characterization and Regulation in Response to Ovarian Steroid Treatment*
Abstract
Tachykinin neuropeptides, such as substance P, are localized to a population of sensory fibers that innervate the mammalian female reproductive tract. In the present study, we have characterized tachykinin NK1 receptor (NK1R), NK2 receptor (NK2R), and NK3 receptor (NK3R) gene expression by semiquantitative RT-PCR in uteri from ovariectomized rats and studied their regulation in response to 17beta-estradiol (E2), progesterone (P4), or a combination of both. In addition, we analyzed the expression and regulation of the neutral endopeptidase 24.11 (NEP), the most important enzyme involved in tachykinin degradation in the rat uterus. In uteri from control (olive oil-treated) rats, RT-PCR assays revealed single bands corresponding to the expected product sizes encoding complementary DNA for NK1R (232 bp), NK2R (491 bp), NK3R (325 bp), and NEP (221 bp). The identity of the amplified fragments was confirmed by DNA sequence analysis. Compared with control rats, NK1R messenger RNA (mRNA) was increased by 2-fold in uteri from rats treated with E2, was decreased by 3.3-fold in rats treated with P4, and was decreased by 1.8-fold in rats treated with both E2 and P4. Uterine NK2R mRNA levels were not altered by any steroid treatment. E2 treatment decreased by 15-fold NK3R mRNA. P4 was without effect if administered alone and did not influence the E2-induced decrease in NK3R mRNA. NEP mRNA levels were about 4-fold lower in E2-treated than in P4-treated rats. Functional studies were carried out in uteri from E2- or P4-treated ovariectomized rats to characterize the contractile response evoked by the selective tachykinin receptor agonists [Sar9Met(O2)11]substance P (NK1R selective), [Nle10]NKA-(4-10) (NK2R selective), and [MePhe7]NKB (NK3R selective) in the presence of the NEP inhibitor phosphoramidon (1 microM). A marked correlation was observed between the magnitude of the contractile response to each agonist and the level of expression determined by RT-PCR for each tachykinin receptor. The present findings show that tachykinin NK1R, NK2R, NK3R, and NEP are expressed in the rat uterus and that ovarian steroids differentially regulate their expression.
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NK1R is expressed in human and rodent uterus, as are CRLR and RAMP1.
“NK1R is expressed in human and rodent uterus66–69, so are CRLR and RAMP170.”
From Neuropeptides Substance P and Calcitonin Gene Related Peptide Accelerate the Development and Fibrogenesis of Endometriosis (2019) · cites this paper as [68]
Expression of NK1R and SP-coding gene TAC1 is upregulated by estrogen and TNF-α.
“The expression of NK1R and SP-coding gene TAC1 is reported to be upregulated by estrogen68,71 and TNF-α44.”
From Neuropeptides Substance P and Calcitonin Gene Related Peptide Accelerate the Development and Fibrogenesis of Endometriosis (2019) · cites this paper as [68]
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Self-citationvan der Goes, M. C., Straub, R. H., Wenting, M. J. G., Capellino, S., Jacobs, J. W. G., Jahangier, Z. N., Rauch, L., Bijlsma, J. W. J., & Lafeber, F. P. J. G. (2012) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2011-201019 · Cited by 12 · see citing works
Grobe, J. L., & Katovich, M. J. (2005) · Regulatory Peptides · doi:10.1016/j.regpep.2005.09.018 · Cited by 12 · see citing works
Hormonal Regulation of the Contractile Response Induced by Okadaic Acid in the Rat Uterus
Trujillo, M., Candenas, L., Cintado, C. G., Magraner, J., Fernandez, J., Martín, J. D., & Pinto, F. M. (2001) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)38825-1 · Cited by 12 · see citing works
Self-citationGonzález-Santana, A., Marrero-Hernández, S., Dorta, I., Hernández, M., Pinto, F. M., Báez, D., Bello, A. R., Candenas, L., & Almeida, T. A. (2016) · Fertility and Sterility · doi:10.1016/j.fertnstert.2016.07.007 · Cited by 11 · see citing works
Self-citationIncreased formation of corpora lutea in neurokinin 1‐receptor deficient mice
Löffler, S., Schulz, A., Hunt, S. P., & Spanel‐Borowski, K. (2004) · Molecular Reproduction and Development · doi:10.1002/mrd.20093 · Cited by 11 · see citing works
Zhang, B., Muneta, T., Yagishita, K., & Sekiya, I. (2006) · Knee Surgery Sports Traumatology Arthroscopy · doi:10.1007/s00167-005-0707-9 · Cited by 11 · see citing works
Elliott, J., Wagner, A. F., & Lysle, D. T. (2006) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2006.08.011 · Cited by 10 · see citing works
Mechanism of uterine vascular refractoriness to endothelin-1 in pregnant sheep
McElvy, S. S., Greenberg, S. G., Mershon, J. L., Yang, D. S., Magill, C., & Clark, K. E. (2001) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.2001.281.2.h804 · Cited by 10 · see citing works
Functional characterisation of hemokinin-1 in mouse uterus
Patak, E., Pennefather, J. N., Gozali, M., Candenas, L., Kerr, K. P., Exintaris, B., Ziccone, S., Potteck, H., Chetty, N., Page, N., et al. (2008) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2008.10.036 · Cited by 7 · see citing works
Self-citationBlasco, V., Pinto, F. M., Fernández‐Atutxa, A., Prados, N., Sánchez, M. F., & Candenas, L. (2022) · Reproductive Sciences · doi:10.1007/s43032-022-00998-9 · Cited by 6 · see citing works
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Pinto, F. M., Bello, A. R., Gallardo-Castro, M., Valladares, F., Almeida, T. A., Tena‐Sempere, M., & Candenas, L. (2015) · Biology of Reproduction · doi:10.1095/biolreprod.115.130617 · Cited by 4 · see citing works
Self-citationDifferential expression of amiloride-sensitive NA+ channel subunits messenger RNA in the rat uterus
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Self-citationExpression of NK1 receptor at the protein and mRNA level in the porcine female reproductive system
Bukowski, R. (2014) · Polish Journal of Veterinary Sciences · doi:10.2478/pjvs-2014-0068 · Cited by 3 · see citing works
Williams, M. J., Hamlin, G. P., Nimmo, A. J., & Crane, L. H. (2003) · Reproduction Fertility and Development · doi:10.1071/rd03021 · Cited by 3 · see citing works
Smooth muscle neurokinin-2 receptors mediate contraction in human saphenous veins
Mechiche, H., Grassin‐Delyle, S., Pinto, F. M., Buenestado, A., Candenas, L., & Devillier, P. (2011) · Pharmacological Research · doi:10.1016/j.phrs.2011.01.010 · Cited by 1 · see citing works
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Sparling, B. A. T. E. (2017) · The Atrium (University of Guelph) · Cited by 1 · see citing works
Role of Nerve Fibres in Endometriosis
Tokushige, N. (2014) · Springer eBooks · doi:10.1007/978-4-431-54421-0_13
THE ROLE OF ANGIOTENSIN-(1-7) IN CARDIOVASCULAR PHYSIOLOGY
Grobe, J. L. (2006)
Tusset, C., Noel, S. D., Trarbach, E. B., Silveira, L. F. G., Jorge, A. A. L., Brito, V. N., Cukier, P., Seminara, S. B., Mendonca, B. B., Kaiser, U. B., et al. (2012)
Pinto, F. M., & Candenas, L. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-801238-3.99364-4
Self-citation
- Authors
- Pinto, F. M., Armesto, C. P., Magraner, J., Trujillo, M., MartÍn, J. D., & Luz Candenas, M.
- Affiliations
- Universidad de La Laguna (ES)
- Centro de Investigaciones Científicas Isla de La Cartuja, Instituto de Investigaciones Químicas, 41092 Sevilla, Spain; and Departamento de Genética, Facultad de Biología, Universidad de La Laguna, 38206 Tenerife, Spain
- Corresponding author
- Pinto, Francisco M.
- ORCID
- Pinto, Francisco M.
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 1999-06-01
- Volume
- 140
- Issue
- 6
- Pages
- 2526-2532
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- OpenAlex
- W2105604596
- Cited by
- 70
- References
- 40
- Citations by year
- 2022: 1 · 2020: 1 · 2019: 2 · 2018: 1 · 2017: 1 · 2016: 2 · 2015: 1 · 2014: 5 · 2013: 2 · 2012: 5
- FWCI
- 1.81
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Generalitat Valenciana
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Keywords
- tachykinin receptors, neurokinin-1 receptor, NK2 receptor, NK3 receptor, neutral endopeptidase 24.11, uterus, estradiol, progesterone, ovarian steroids, gene expression regulation, substance P, neurokinin A, neurokinin B, phosphoramidon, uterine contractility, ovariectomized rats
- MeSH terms
- Animals, Female, Gene Expression Regulation, RNA, Messenger, Gonadal Steroid Hormones, Uterus, Neprilysin, Rats, Wistar, Receptors, Tachykinin, Reverse Transcriptase Polymerase Chain Reaction, Rats
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