This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Saiardi, A. Articles by Borrelli, E. Search for Related Content PubMed PubMed Citation Articles by Saiardi, A. Articles by Borrelli, E.

Absence of Dopaminergic Control on Melanotrophs Leads to Cushing’s-Like Syndrome in Mice

Institut de Génétique et de Biologie Moléculaire et Cellulaire Centre Nationale de la Recherche Scientifique/INSERM/ Université Louis Pasteur BP 163 67404 Illkirch Cedex C.U. de Strasbourg, France

Dopamine negatively regulates POMC gene expression in melanotrophs of the intermediate lobe of the pituitary gland. The dopaminergic receptor involved in this control is the dopamine D2 receptor (D2R). The principal products of the POMC gene in melanotrophs are ß-endorphin and -MSH. POMC is differently processed in the corticotrophs, where it is not regulated by dopamine and it is principally processed into ACTH. Here we show that D2R-deficient mice have increased POMC expression and intermediate lobe hypertrophy. Strikingly, D2R-deficient mice have unexpected elevated ACTH levels with a corresponding increase of corticosteroids and consequent hypertrophy of the adrenal gland. This phenotype is reminiscent of Cushing’s syndrome in humans. Interestingly, we show that the elevation in ACTH levels is due to an aberrant processing of POMC in melanotrophs. Indeed, we demonstrate that in addition to controlling POMC gene expression in these cells, dopamine, by modulating the expression of the convertases involved in the cleavage of the POMC prohormone, strictly regulates its processing. These results reveal a key role for dopamine in the control of POMC-derived peptides and furthermore indicate an implication of the dopaminergic system in the genesis of Cushing’s syndrome.

This article has been cited by other articles:

				S.-N. Lee, B. Peng, R. Desjardins, J. E Pintar, R. Day, and I. Lindberg Strain-specific steroidal control of pituitary function J. Endocrinol., March 1, 2007; 192(3): 515 - 525. [Abstract] [Full Text] [PDF]

				M. Bjorkqvist, A. Petersen, K. Bacos, J. Isaacs, P. Norlen, J. Gil, N. Popovic, F. Sundler, G. P. Bates, S. J. Tabrizi, et al. Progressive alterations in the hypothalamic-pituitary-adrenal axis in the R6/2 transgenic mouse model of Huntington's disease Hum. Mol. Genet., May 15, 2006; 15(10): 1713 - 1721. [Abstract] [Full Text] [PDF]

				M. Kobayashi, C. Iaccarino, A. Saiardi, V. Heidt, Y. Bozzi, R. Picetti, C. Vitale, H. Westphal, J. Drago, and E. Borrelli Simultaneous absence of dopamine D1 and D2 receptor-mediated signaling is lethal in mice PNAS, August 3, 2004; 101(31): 11465 - 11470. [Abstract] [Full Text] [PDF]

				M. S. Sarac, A. W. Zieske, and I. Lindberg The Lethal Form of Cushing's in 7B2 Null Mice Is Caused by Multiple Metabolic and Hormonal Abnormalities Endocrinology, June 1, 2002; 143(6): 2324 - 2332. [Abstract] [Full Text] [PDF]

				V. Laurent, A. Kimble, B. Peng, P. Zhu, J. E. Pintar, D. F. Steiner, and I. Lindberg Mortality in 7B2 null mice can be rescued by adrenalectomy: Involvement of dopamine in ACTH hypersecretion PNAS, February 14, 2002; (2002) 261715099. [Abstract] [Full Text] [PDF]

				A. Slominski, J. Wortsman, T. Luger, R. Paus, and S. Solomon Corticotropin Releasing Hormone and Proopiomelanocortin Involvement in the Cutaneous Response to Stress Physiol Rev, July 1, 2000; 80(3): 979 - 1020. [Abstract] [Full Text] [PDF]

				V. Laurent, A. Kimble, B. Peng, P. Zhu, J. E. Pintar, D. F. Steiner, and I. Lindberg Mortality in 7B2 null mice can be rescued by adrenalectomy: Involvement of dopamine in ACTH hypersecretion PNAS, March 5, 2002; 99(5): 3087 - 3092. [Abstract] [Full Text] [PDF]