MEMBRANE-RECEPTORS AND G-PROTEINS IN ANTE RIOR-PITUITARY-CELLS

Dopamine receptors of D2 type present on lactotroph cells are coupled to a large series of transduction mechanisms. Beside their negative co upling with adenylate cyclase, they are also coupled with potassium an d calcium channels, leading to a decreased intracellular calcium conce ntration. In addition, D2 dopamine receptors also modulate phospholipa se activities. Dopamine inhibits inositol phosphate production, throug h two distinct mechanisms. One of them could represent a direct negati ve coupling with phospholipase C. All these transduction mechanisms of the D2 dopamine receptors implicate G proteins sensitive to pertussis toxin. In contrast, these receptors are negatively coupled to phospho lipase A2 through G proteins insensitive to this toxin. Both isoforms of the D2 dopamine receptor, generated by alternate splicing of a sing le gene are present in lactotroph cells. After transfection in CH4C1 c ells the two isoforms are coupled with adenylate cyclase while only th e shortest isoform appears negatively coupled to phospholipase C. Func tional D2 dopamine receptors are present in human prolactinomas. Resis tance to bromocriptine therapy is associated with a decrease density o f these receptors in the tumor. In addition, the ratio of the two rece ptor isoforms (measured by PCR) is different in responsive and resista nt tumors. Furthermore, the activity of Gi/Go proteins coupled to aden ylate cyclase appears also affected in resistant tumors. Resistance to bromocriptine therapy appears thus to involve multiple changes at the different levels of the multiple mechanisms of action of dopamine on lactotroph cells.