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

Endocrinology. 2024 Oct 30;165(12):bqae144. doi: 10.1210/endocr/bqae144.

Abstract

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.

Keywords: B2R; D2R; heteromers; pituitary; prolactinoma; signaling.

MeSH terms

  • Adenoma / genetics
  • Adenoma / metabolism
  • Adenoma / pathology
  • Adult
  • Animals
  • Dopamine / metabolism
  • Dopamine Agonists / pharmacology
  • Drug Resistance, Neoplasm
  • Female
  • HEK293 Cells
  • Humans
  • Male
  • Middle Aged
  • Pituitary Neoplasms* / genetics
  • Pituitary Neoplasms* / metabolism
  • Pituitary Neoplasms* / pathology
  • Prolactinoma* / genetics
  • Prolactinoma* / metabolism
  • Prolactinoma* / pathology
  • Receptors, Dopamine D2* / genetics
  • Receptors, Dopamine D2* / metabolism
  • Signal Transduction

Substances

  • Receptors, Dopamine D2
  • Dopamine
  • Dopamine Agonists
  • DRD2 protein, human