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PKA regulatory subunit 1A inactivating mutation induces serotonin signaling in primary pigmented nodular adrenal disease
Zakariae Bram, … , Jérôme Bertherat, Hervé Lefebvre
Zakariae Bram, … , Jérôme Bertherat, Hervé Lefebvre
Published September 22, 2016
Citation Information: JCI Insight. 2016;1(15):e87958. https://doi.org/10.1172/jci.insight.87958.
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Research Article Endocrinology

PKA regulatory subunit 1A inactivating mutation induces serotonin signaling in primary pigmented nodular adrenal disease

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Abstract

Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of ACTH-independent hypercortisolism. The disease is primarily caused by germline mutations of the protein kinase A (PKA) regulatory subunit 1A (PRKAR1A) gene, which induces constitutive activation of PKA in adrenocortical cells. Hypercortisolism is thought to result from PKA hyperactivity, but PPNAD tissues exhibit features of neuroendocrine differentiation, which may lead to stimulation of steroidogenesis by abnormally expressed neurotransmitters. We hypothesized that serotonin (5-HT) may participate in the pathophysiology of PPNAD-associated hypercortisolism. We show that PPNAD tissues overexpress the 5-HT synthesizing enzyme tryptophan hydroxylase type 2 (Tph2) and the serotonin receptors types 4, 6, and 7, leading to formation of an illicit stimulatory serotonergic loop whose pharmacological inhibition in vitro decreases cortisol production. In the human PPNAD cell line CAR47, the PKA inhibitor H-89 decreases 5-HT4 and 5-HT7 receptor expression. Moreover, in the human adrenocortical cell line H295R, inhibition of PRKAR1A expression increases the expression of Tph2 and 5-HT4/6/7 receptors, an effect that is blocked by H-89. These findings show that the serotonergic process observed in PPNAD tissues results from PKA activation by PRKAR1A mutations. They also suggest that Tph inhibitors may represent efficient treatments of hypercortisolism in patients with PPNAD.

Authors

Zakariae Bram, Estelle Louiset, Bruno Ragazzon, Sylvie Renouf, Julien Wils, Céline Duparc, Isabelle Boutelet, Marthe Rizk-Rabin, Rossella Libé, Jacques Young, Dennis Carson, Marie-Christine Vantyghem, Eva Szarek, Antoine Martinez, Constantine A. Stratakis, Jérôme Bertherat, Hervé Lefebvre

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Figure 1

Serotonin (5-HT) production by PPNAD tissues.

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Serotonin (5-HT) production by PPNAD tissues.
(A) Tryptase immunoreactiv...
(A) Tryptase immunoreactivity (Tryp) in normal adrenal and PPNAD tissue from patient 13 (P13). Mast cells are designated by arrows. (B) Mast cell density in PPNAD tissues (n = 19) compared with normal adrenals (NA) (n = 7). (C) TPH1 and TPH2 mRNA levels in explants of NA and PPNAD tissues. PPNAD with PRKAR1A (red), PDE11A (green), and no (black) mutations. mRNA expression levels were normalized to PPIA. (D) Tph2, Tph, and 5-HT immunoreactivities in normal adrenals. Immunoreactive cells are designated by arrows. (E) Tph2, Tph, 5-HT, 17α-hydroxylase (17-OH), and steroidogenic factor 1 (SF1) immunoreactivities in PPNAD tissues on a section from P13 (Tph) and consecutive sections from P13 (Tph2, 5-HT, and 17-OH; left panels) and P30 (5-HT and SF1; right panels). In the left column, arrows designate groups of cells coexpressing Tph2, Tph, and 17-OH. In the right column, arrows designate immunopositive cells for Tph, 5-HT, or SF1. (F) HPLC detection of 5-HT in incubation medium of PPNAD explants from P32 (higher panel) and culture medium added with synthetic 5-HT (10–6 M; lower panel). Retention time of synthetic 5-HT (▼). N-methylserotonin was used as an internal standard (arrow). Data were analyzed by using Mann-Whitney U test. **P < 0.01. Ca, capsule; ZG, zona glomerulosa. Scale bars: 50 μm.

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