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      Decreased Expression of the Two D 2 Dopamine Receptor Isoforms in Bromocriptine-Resistant Prolactinomas

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          Abstract

          Bromocriptine or other dopamine agonists are usually effective for the treatment of prolactin-secreting adenomas. Five to 18% of prolactinomas, however, do not respond to such therapy. We have shown previously that such resistance to bromocriptine correlates with reduced binding to the D<sub>2</sub> receptor subtype of dopamine, the major PRL inhibiting factor. In the present work, we demonstrated that reduced binding actually corresponds to decreased expression of the gene coding for the D<sub>2</sub> receptor in the pituitary from bromocriptine-resistant patients, as shown by 4-fold lower levels of the corresponding mRNAs compared to those coding for actin. The existence of two D<sub>2</sub> receptor isoforms, D<sub>2</sub>S and D<sub>2</sub>L generated by alternative splicing, has been described in several tissues, including the pituitary. Both are negatively coupled to adenylyl cyclase and inhibit prolactin secretion, but, in addition, the shortest one (D<sub>2</sub>S) is more efficiently coupled to phospholipase C. Consequently, we also investigated whether expression of a particular D<sub>2</sub> receptor isoform was preferentially affected in resistant adenomas. The proportion of messengers corresponding to the short receptor isoform (D<sub>2</sub>S) was lower in resistant compared to responsive adenomas: D<sub>2</sub>S/D<sub>2</sub>L = 0.74 ± 0.08 and 1.00 ± 0.07, respectively. In parallel, much lower levels of D<sub>2</sub> receptor mRNAs were found in growth hormone-secreting adenomas, with a D<sub>2</sub>S/D<sub>2</sub>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 defects in D<sub>2</sub> dopamine receptor expression and possibly in posttranscriptional splicing.

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          Author and article information

          Journal
          NEN
          Neuroendocrinology
          10.1159/issn.0028-3835
          Neuroendocrinology
          S. Karger AG
          0028-3835
          1423-0194
          1994
          1994
          09 April 2008
          : 60
          : 3
          : 314-322
          Affiliations
          aICNE, UMR 9941 CNRS, Université Aix-Marseille II, Faculté de Médecine Nord, Marseille, bINSERM U159, Centre Paul-Broca, cINSERM U332, ICGM, Paris, dService Endocrinologie et Diabétologie, Lille, France
          Article
          126764 Neuroendocrinology 1994;60:314–322
          10.1159/000126764
          7969790
          © 1994 S. Karger AG, Basel

          Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

          Page count
          Pages: 9
          Categories
          Gonadotropins and Prolactin

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