DECREASED EXPRESSION OF THE 2 D-2 DOPAMINE-RECEPTOR ISOFORMS IN BROMOCRIPTINE-RESISTANT PROLACTINOMAS

Bromocriptine or other dopamine agonists are usually effective for the treatment of prolactin-secreting adenomas. Five to 18% of prolactinom as, however, do not respond to such therapy. We have shown previously that such resistance to bromocriptine correlates with reduced binding to the D-2 receptor subtype of dopamine, the major PRL inhibiting fact or. In the present work, we demonstrated that reduced binding actually corresponds to decreased expression of the gene coding for the D-2 re ceptor in the pituitary from bromocriptine-resistant patients, as show n by 4-fold lower levels of the corresponding mRNAs compared to those coding for actin. The existence of two D-2 receptor isoforms, D2S and D(2)L generated by alternative splicing, has been described in several tissues, including the pituitary. Both are negatively coupled to aden ylyl cyclase and inhibit prolactin secretion, but, in addition, the sh ortest one (D2S) is more efficiently coupled to phospholipase C. Conse quently, we also investigated whether expression of a particular D-2 r eceptor isoform was preferentially affected in resistant adenomas. The proportion of messengers corresponding to the short receptor isoform (D2S) was lower in resistant compared to responsive adenomas: D2S/D(2) L = 0.74 +/- 0.08 and 1.00 +/- 0.07, respectively. In parallel, much l ower levels of D-2 receptor mRNAs were found in growth hormone-secreti ng adenomas, with a D2S/D(2)L ratio comparable to those of both normal human pituitary and bromocriptine-sensitive prolactinomas (1.05 +/- 0 .11). Thus, resistance to bromocriptine therapy seems to involve defec ts in D-2 dopamine receptor expression and possibly in posttranscripti onal splicing.