title: PKA regulatory subunit 1A inactivating mutation induces serotonin signaling in primary pigmented nodular adrenal disease.
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-HT4and 5-HT7receptor expression. Moreover, in the human adrenocortical cell line H295R, inhibition ofPRKAR1Aexpression increases the expression of Tph2 and 5-HT4/6/7receptors, an effect that is blocked by H-89. These findings show that the serotonergic process observed in PPNAD tissues results from PKA activation byPRKAR1Amutations. They also suggest that Tph inhibitors may represent efficient treatments of hypercortisolism in patients with PPNAD.
authors.affiliation: Normandie University, UNIROUEN, INSERM, U982, Laboratoire Differenciation et Communication Neuronale et Neuroendocrine, 76000 Rouen, France.
authors.forename: Zakariae
authors.initials: Z
authors.lastname: Bram
authors.affiliation: Normandie University, UNIROUEN, INSERM, U982, Laboratoire Differenciation et Communication Neuronale et Neuroendocrine, 76000 Rouen, France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Louiset
authors.affiliation: INSERM, U1016, University Paris V, Cochin Institute, Paris, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Ragazzon
authors.affiliation: Normandie University, UNIROUEN, INSERM, U982, Laboratoire Differenciation et Communication Neuronale et Neuroendocrine, 76000 Rouen, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Renouf
authors.affiliation: Normandie University, UNIROUEN, INSERM, U982, Laboratoire Differenciation et Communication Neuronale et Neuroendocrine, 76000 Rouen, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Wils
authors.affiliation: Normandie University, UNIROUEN, INSERM, U982, Laboratoire Differenciation et Communication Neuronale et Neuroendocrine, 76000 Rouen, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Duparc
authors.affiliation: Normandie University, UNIROUEN, INSERM, U982, Laboratoire Differenciation et Communication Neuronale et Neuroendocrine, 76000 Rouen, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Boutelet
authors.affiliation: INSERM, U1016, University Paris V, Cochin Institute, Paris, France.
authors.forename: Marthe
authors.initials: M
authors.lastname: Rizk-Rabin
authors.affiliation: INSERM, U1016, University Paris V, Cochin Institute, Paris, France.
authors.forename: Rossella
authors.initials: R
authors.lastname: Libé
authors.affiliation: University Paris Sud, INSERM Unité 693, Le Kremlin-Bicêtre, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Young
authors.affiliation: Department of Paediatric Endocrinology, Royal Belfast Hospital for Sick Children, Belfast, United Kingdom.
authors.forename: Dennis
authors.initials: D
authors.lastname: Carson
authors.affiliation: CHU Lille, Endocrinology Diabetology and Metabolism, Lille, France.|Univ. Lille, Inserm U1190 - EGID, Lille, France.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Vantyghem
authors.affiliation: Section of Endocrinology and Genetics, PDEGEN, NICHD, Bethesda, Maryland, USA.
authors.forename: Eva
authors.initials: E
authors.lastname: Szarek
authors.affiliation: CNRS UMR6247, INSERM U931, Gred, Clermont Université, Aubière, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Martinez
authors.affiliation: Section of Endocrinology and Genetics, PDEGEN, NICHD, Bethesda, Maryland, USA.
authors.forename: Constantine A
authors.initials: CA
authors.lastname: Stratakis
authors.affiliation: INSERM, U1016, University Paris V, Cochin Institute, Paris, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bertherat
authors.affiliation: Normandie University, UNIROUEN, INSERM, U982, Laboratoire Differenciation et Communication Neuronale et Neuroendocrine, 76000 Rouen, France.|Department of Endocrinology, CHU Rouen, Rouen, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Lefebvre
mesh_terms: D000293:Adolescent; D000303:Adrenal Cortex Diseases / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011985:Receptors, Serotonin / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D015398:Signal Transduction; D014365:Tryptophan Hydroxylase / Q000378:metabolism*; D055815:Young Adult
chemical_list: D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; C517834:PRKAR1A protein, human; D011985:Receptors, Serotonin; D012701:Serotonin; C494784:TPH2 protein, human; D014365:Tryptophan Hydroxylase