B2R overexpression in resistant prolactinomas promotes B2R-D2R dimerization, with B2R precluding D2R signalling generating resistance to D2R agonists

Alejandra Ines Abeledo-Machado; Josep Argerich; Dana Bornancini; Agustin Yaneff; Carina Shayo; Mariela Gironacci; Francisco Ciruela; Graciela Diaz-Torga

doi:10.1530/endoabs.110.OC4.2

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Endocrine Abstracts (2025) 110 OC4.2 | DOI: 10.1530/endoabs.110.OC4.2

ECEESPE2025 Oral Communications Oral Communications 4: Pituitary, Neuroendocrinology and Puberty Part 1 (6 abstracts)

B2R overexpression in resistant prolactinomas promotes B2R-D2R dimerization, with B2R precluding D2R signalling generating resistance to D2R agonists

Alejandra Inés Abeledo-Machado ¹ , Josep Argerich ² , Dana Bornancini ¹ , Agustin Yaneff ³ , Carina Shayo ¹ , Mariela Gironacci ⁴ , Francisco Ciruela ² & Graciela Diaz-Torga ^1,5

Author affiliations

¹Instituto de Biologia y Medicina Experimental, CONICET, Buenos Aires, Argentina; ²Pharmacology Unit, Department of Pathology and Experimental Therapeutics, School of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, 08907 L’Hospitalet de Llobregat, Spain, 08907 L’Hospitalet de Llobregat, Spain, Neuropharmacology & Pain Group, Neuroscience Program, Bellvitge Institute for Biomedical Research, Barcelona, Spain; ³Instituto de Investigaciones Farmacológicas (ININFA-UBA-CONICET), Buenos Aires, Argentina; ⁴Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Química Biológica and IQUIFIB (UBA-CONICET),, Buenos Aires, Argentina; ⁵Instituto de Biologia y Medicina Experimental, Laboratorio de Fisiopatologia Hormonal, Buenos Aires, Argentina

JOINT3779

Among the pituitary tumours PROLACTINOMAS, are the most frequently observed in the clinic. The dopamine receptor 2 (D2R) agonists represent a highly effective first-line therapy. However, between 15 and 20% of patients do not respond to the treatment or become resistant. These RESISTANT prolactinomas represent a major challenge for clinical management as there are no alternative treatments. During the last few years, our focus has been on why D2R doesn’t work. Then we start studying whether D2R dimerization disrupts its signalling in lactotrophs promoting resistance to D2R agonists. The bradykinin receptor type 2 (B2R) is overexpressed in prolactinomas. We postulated that the increased B2R expression in prolactinomas could facilitate D2R-B2R dimerization disturbing D2R signalling, promoting resistance to D2R agonists. We first characterized the bradykinin receptors in the pituitary, and we found that B2R is the most expressed, mainly in lactotrophs cells. Then, the formation of B2R-D2R complexes in cultured cells transiently expressing both receptors was validated using the NanoBiT technology. Interestingly, while the stimulation of D2R did not alter B2R-induced intracellular calcium mobilization, B2R stimulation abolished D2R signalling (modulation of cAMP levels). The existence of B2R-D2R complexes in human pituitary adenomas biopsies was evaluated. B2R-D2R complexes were detected, using the ALPHALisa approach, in human prolactinomas and nonfunctioning pituitary adenomas (NFPA), but not in mixed (prolactin + growth hormone) secreting adenomas. These results suggest that overexpression of B2R in resistant prolactinomas may promote the formation of B2R-D2R complexes, with B2R disrupting D2R signalling, generating resistance to D2R agonists.