2. Academic Validation
  3. Characterization of functionally relevant G protein-coupled receptors in endometriotic epithelial cells

Characterization of functionally relevant G protein-coupled receptors in endometriotic epithelial cells

  • Cell Signal. 2025 Sep:133:111876. doi: 10.1016/j.cellsig.2025.111876.
Matteo Prisinzano 1,  Isabelle Seidita 2,  Paola Bruni 3,  Felice Petraglia 4,  Caterina Bernacchioni 5,  Dagmar Meyer Zu Heringdorf 6,  Chiara Donati 7
Affiliations

Affiliations

  • 1 Department of Experimental and Clinical Biomedical Sciences "M. Serio", University of Florence, Viale Morgagni 50, 50134 Florence, Italy; Institut für Allgemeine Pharmakologie und Toxikologie, Goethe-Universität Frankfurt, Universitätsklinikum, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. Electronic address: matteo.prisinzano@unifi.it.
  • 2 Department of Experimental and Clinical Biomedical Sciences "M. Serio", University of Florence, Viale Morgagni 50, 50134 Florence, Italy. Electronic address: isabelle.seidita@unifi.it.
  • 3 Department of Experimental and Clinical Biomedical Sciences "M. Serio", University of Florence, Viale Morgagni 50, 50134 Florence, Italy. Electronic address: paola.bruni@unifi.it.
  • 4 Department of Experimental and Clinical Biomedical Sciences "M. Serio", University of Florence, Viale Morgagni 50, 50134 Florence, Italy. Electronic address: felice.petraglia@unifi.it.
  • 5 Department of Experimental and Clinical Biomedical Sciences "M. Serio", University of Florence, Viale Morgagni 50, 50134 Florence, Italy. Electronic address: caterina.bernacchioni@unifi.it.
  • 6 Institut für Allgemeine Pharmakologie und Toxikologie, Goethe-Universität Frankfurt, Universitätsklinikum, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. Electronic address: heringdorf@med.uni-frankfurt.de.
  • 7 Department of Experimental and Clinical Biomedical Sciences "M. Serio", University of Florence, Viale Morgagni 50, 50134 Florence, Italy. Electronic address: chiara.donati@unifi.it.
PMID: 40381972 DOI: 10.1016/j.cellsig.2025.111876
Abstract

Endometriosis is a chronic inflammatory disease characterized by the invasion of endometrial cells outside the uterine cavity. Current treatments for the disease, whose typical symptoms are pain and infertility, are unsatisfactory, relying on the surgical removal of the lesions and hormonal therapies with high symptom relapse and collateral effects, respectively. The aim of the present study was to exploit the rationale for G protein-coupled receptors (GPCRs) as non-hormonal therapeutic targets for this disease. To this end, human endometriotic epithelial cells 12Z were employed to characterize GPCR-mediated increases in intracellular CA2+ concentrations ([CA2+]i) using fluo-4, and cell invasion was measured using Boyden chamber assays. The results showed that the GPCR ligands oxytocin, bradykinin, histamine, lysophosphatidic acid, and sphingosine 1-phosphate (S1P) efficiently increased [CA2+]i and induced cell invasion in endometriotic cells. In contrast, neuropeptide S, previously identified as a pro-invasive mediator, did not increase [CA2+]i in 12Z cells. Notably, pretreatment with pertussis toxin significantly reduced S1P-dependent [CA2+]i increase and cell invasion, highlighting the involvement of Gi-mediated signaling. Employing specific agonists and/or antagonists of S1P receptor isoforms, we demonstrated that S1P1/S1P3/S1P5, but not S1P2/S1P4 mediated the [CA2+]i increases in this cellular model. Moreover, activation of S1P1/S1P4/S1P5, but not S1P2/S1P3, efficiently stimulated cell invasion. Taken together, we identified several GPCRs that are functionally relevant in human endometriotic epithelial cells and may potentially serve as targets for non-hormonal therapy of endometriosis.

Keywords

Cell invasion; Endometriosis; G-protein coupled receptor ligands; Intracellular calcium levels; Non-hormonal targets; Sphingosine 1-phosphate receptors.

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