ICEECE2012 Oral Communications Adrenal Clinical (6 abstracts)
Activation of the PKA pathway triggers formation of an illicit serotonergic regulatory loop in primary pigmented nodular adrenal disease (PPNAD) tissues associated with Cushing’s syndrome
Z. Bram 1 , S. Renouf 1 , C. Duparc 1 , B. Ragazzon 2 , R. Libe 2 , A. Martinez 3 , C. Stratakis 4 , J. Bertherat 2 , E. Louiset 1 & H. Lefebvre 1,
1Institute for Biomedical Research and Innovation, University of Rouen, Rouen, France; 2University Paris V, Cochin Institute, Paris, France; 3Clermont University, Aubiere, France; 4NIH, Bethesda, Maryland, USA; 5Institute for Biomedical Research and Innovation, University Hospital of Rouen, Rouen, France.
In the normal adrenal gland, serotonin (5-HT) stimulates cortisol secretion through activation of 5-HT4 receptors whereas, in some macronodular adrenal hyperplasia tissues, the corticotropic effect of 5-HT is mediated by ectopic 5-HT7 receptors. The aim of the present study was to investigate the role of 5-HT in the control of cortisol secretion in PPNAD tissues from 12 patients by using molecular, immunohistochemical and pharmacological approaches. RT-PCR studies revealed overexpression of the genes encoding tryptophan hydroxylase, the key enzyme of 5-HT synthesis, and the 5-HT4 and 5-HT7 receptors, in comparison with normal adrenals. Tryptophan hydroxylase was detected in hyperplastic nodules by immunohistochemistry. 5-HT dose-dependently increased cortisol production by PPNAD cells derived from 6 patients. The potency and efficacy of 5-HT to stimulate cortisol were higher in PPNAD than in normal adrenocortical cells. 5-HT was also able to increase expression of the CYP11B1 gene, which encodes the steroidogenic enzyme 11alpha-hydroxylase, in the PPNAD immortalized cell line LT2. Both the 5-HT4 receptor antagonist GR113808 and the 5-HT7 receptor antagonist SB269970 significantly inhibited the stimulatory effect of 5-HT on cortisol by reducing the potency and efficacy of the indolamine. These data indicate that, in PPNAD cells, the stimulatory action of 5-HT on cortisol release is mediated by both the eutopic 5-HT4 receptor and an ectopic 5-HT7 receptor. In most patients, PPNAD results from inactivating mutations of the PRKAR1A gene which cause enhancement of the PKA pathway. In the adrenocortical cell line H295R, inhibition of PRKAR1A gene expression markedly stimulated expression of tryptophan hydroxylase, 5-HT4 and 5-HT7 receptor mRNAs. Taken together, our results show that activation of the PKA pathway triggers formation of an illicit serotonergic regulatory loop in PPNAD tissues associated with Cushing’s syndrome. This work was supported by INSERM U982, the Carney Complex network and ANR Genopat 2008.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This work was supported, however funding details are unavailable.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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