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

Area of Science:

• Endocrinology
• Molecular Biology
• Oncology

Background:

• Prolactinomas are common pituitary tumors treated with dopamine D2 receptor (D2R) agonists.
• Approximately 20% of prolactinomas exhibit resistance to these therapies, necessitating alternative treatments.
• The molecular basis for dopamine resistance in prolactinomas is not fully understood, but altered D2R signaling is suspected.

Purpose of the Study:

• To investigate the potential physical and functional interaction between dopamine D2 receptor (D2R) and bradykinin receptor type 2 (B2R) in prolactinomas.
• To determine if B2R overexpression contributes to resistance against D2R agonist therapy in prolactinomas.

Main Methods:

• Utilized NanoBiT technology to detect B2R-D2R complex formation in cultured cells.
• Assessed D2R signaling via cAMP modulation and B2R-induced calcium mobilization.
• Employed ALPHALisa to evaluate B2R-D2R complex presence in human pituitary adenoma biopsies.

Main Results:

• Validated the formation of B2R-D2R complexes in cells co-expressing both receptors.
• Observed that B2R stimulation inhibited D2R signaling (cAMP modulation), while D2R stimulation did not affect B2R signaling.
• Detected B2R-D2R complexes in human prolactinomas and nonfunctioning pituitary adenomas, but not in mixed-secreting adenomas.

Conclusions:

• Overexpression of B2R in resistant prolactinomas may lead to B2R-D2R complex formation.
• These complexes appear to impair D2R signaling, contributing to resistance to dopamine-based therapies.
• This interaction presents a potential therapeutic target for dopamine-resistant prolactinomas.