Structural differences between dopamine D2 receptors present in a rat pituitary adenoma and in transplantable rat pituitary tumors 7315a and MtTW15.
We have investigated the structure of dopamine (DA) D2 receptors present in an estrone-induced, prolactin (PRL)-secreting, DA-sensitive adenoma and in two PRL-secreting and DA-insensitive transplantable tumors 7315a and MtTW15, in order to identify better the anomalies present in DA-resistant lactotrophs. D2 receptors were found in both a high- and a low-affinity state in adenomatous lactotrophs as shown by displacement studies with the agonist N-propylnorapomorphine (NPA), but only in the low-affinity state in the two DA-resistant tumors. Treatment with the alkylating agent N-ethylmaleimide induced a disappearance of the high-affinity state of the D2 receptor in the adenoma and a reduction in receptor concentration, but did not have any effect on the affinity of receptors present in DA-resistant tumors. Moreover, target size analysis and radiation inactivation studies of D2 receptors, using membranes preincubated with NPA and [3H]spiperone as ligand or using [3H]NPA as ligand on membranes preparations, have shown the presence of distinct structural differences between adenomatous and tumoral D2 receptors and between the two tumoral receptors themselves; these results suggest that the normal functional unit of the D2 receptor is a dimer associated with a guanine nucleotide-binding protein (G protein) subunit and that tumoral D2 receptors may exist in various polymeric forms unassociated with G proteins. The anomalies found to be present in tumoral D2 receptor complexes may be responsible for the insensitivity of these tumors to dopaminergic agonists' inhibitory activity on PRL release and tumor growth.
Bouvier
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Research Unit on Reproductive and Developmental Biology, Hôpital Sainte-Justine, Montréal, Québec, Canada.
Lagacé
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Potier
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Collu
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R
D000236:Adenoma / Q000378:metabolism*; D000818:Animals; D001058:Apomorphine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive; D002352:Carrier Proteins / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D015259:Dopamine Agents; D005033:Ethylmaleimide / Q000494:pharmacology; D009368:Neoplasm Transplantation; D010911:Pituitary Neoplasms / Q000378:metabolism*; D051381:Rats; D011954:Receptors, Dopamine / Q000378:metabolism*; D017448:Receptors, Dopamine D2; D012995:Solubility; D013134:Spiperone / Q000378:metabolism
D002352:Carrier Proteins; D015259:Dopamine Agents; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D013134:Spiperone; C009074:N-n-propylnorapomorphine; D001058:Apomorphine; D005033:Ethylmaleimide