B2R-D2R Interaction in Prolactinomas and Nonfunctional Adenomas: Impact on Dopamine Resistance

Prolactinomas, the most common pituitary-secreting adenomas, can be effectively treated with dopamine D2 receptor (D2R) agonists. However, a subset of them (∼20%) are resistant to dopamine-based therapies and require extirpation. The molecular mechanisms underlying their escape from dopaminergic regulation are not fully elucidated and may include alterations in D2R signaling. D2R can heteromerize with other G protein-coupled receptors, resulting in modulation of dopaminergic signaling. Because the bradykinin receptor type 2 (B2R) is overexpressed in prolactinomas, we interrogated whether this dopaminergic dysregulation observed in some prolactinomas may depend on a physical and functional interaction between D2R and B2R. The formation of B2R-D2R complexes in cultured cells transiently expressing both receptors was validated using NanoBiT technology. Interestingly, although D2R stimulation did not alter B2R-induced intracellular calcium mobilization, B2R stimulation abolished D2R signaling through modulation of cAMP. The existence of B2R-D2R complexes in pituitary adenomas biopsies was evaluated using an ALPHALisa approach. Importantly, B2R-D2R complexes were detected in human prolactinomas and nonfunctioning pituitary adenomas, 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 precluding D2R signaling, thus generating resistance to D2R agonists.