D. Cussac et al., MEMBRANE-RECEPTORS AND G-PROTEINS IN ANTE RIOR-PITUITARY-CELLS, Comptes rendus des seances de la Societe de biologie et de ses filiales, 187(1), 1993, pp. 14-23
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.