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PKA regulatory subunit 1A inactivating mutation induces serotonin signaling in primary pigmented nodular adrenal disease
- Source :
- JCI Insight, JCI Insight, American Society for Clinical Investigation, 2016, 1 (15), pp.e87958. ⟨10.1172/jci.insight.87958⟩, JCI Insight, 2016, 1 (15), pp.e87958. ⟨10.1172/jci.insight.87958⟩, JCI Insight, American Society for Clinical Investigation, 2016, 1 (15), ⟨10.1172/jci.insight.87958⟩
- Publication Year :
- 2016
- Publisher :
- HAL CCSD, 2016.
-
Abstract
- International audience; 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.
- Subjects :
- 0301 basic medicine
Male
MESH: Signal Transduction
Receptor expression
[SDV]Life Sciences [q-bio]
Tryptophan Hydroxylase
0302 clinical medicine
MESH: Child
[SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB]
Child
PRKAR1A
ComputingMilieux_MISCELLANEOUS
MESH: Middle Aged
TPH2
General Medicine
Middle Aged
[SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism
3. Good health
MESH: Young Adult
Child, Preschool
Female
Signal transduction
Signal Transduction
Research Article
Adrenal Cortex Diseases
Adult
medicine.medical_specialty
Serotonin
MESH: Receptors, Serotonin
MESH: Mutation
Adolescent
Cyclic AMP-Dependent Protein Kinase RIalpha Subunit
030209 endocrinology & metabolism
[SDV.CAN]Life Sciences [q-bio]/Cancer
[SDV.BC]Life Sciences [q-bio]/Cellular Biology
Biology
Serotonergic
Cell Line
03 medical and health sciences
Young Adult
Internal medicine
[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN]
medicine
Humans
MESH: Cyclic AMP-Dependent Protein Kinase RIalpha Subunit
Protein kinase A
MESH: Adolescent
MESH: Humans
MESH: Adrenal Cortex Diseases
MESH: Child, Preschool
MESH: Adult
[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology
Tryptophan hydroxylase
MESH: Male
MESH: Tryptophan Hydroxylase
MESH: Cell Line
[SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics
030104 developmental biology
Endocrinology
[SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis
Receptors, Serotonin
Mutation
MESH: Serotonin
MESH: Female
Primary pigmented nodular adrenocortical disease
Subjects
Details
- Language :
- English
- ISSN :
- 23793708
- Database :
- OpenAIRE
- Journal :
- JCI Insight, JCI Insight, American Society for Clinical Investigation, 2016, 1 (15), pp.e87958. ⟨10.1172/jci.insight.87958⟩, JCI Insight, 2016, 1 (15), pp.e87958. ⟨10.1172/jci.insight.87958⟩, JCI Insight, American Society for Clinical Investigation, 2016, 1 (15), ⟨10.1172/jci.insight.87958⟩
- Accession number :
- edsair.doi.dedup.....54122e209af72f6b75250a8b64f8281e