Expression of serotonin7 receptor and coupling of ectopic receptors to protein kinase A and ionic currents in adrenocorticotropin-independent macronodular adrenal hyperplasia causing Cushing's syndrome.
BACKGROUND
In ACTH-independent macronodular adrenal hyperplasia (AIMAH) causing Cushing's syndrome, cortisol secretion is controlled by illegitimate membrane receptors.


OBJECTIVE
The aim of the present study was to characterize the pharmacological properties and the transduction mechanisms of illegitimate receptors, i.e. receptors for serotonin (5-HT), gastric inhibitory polypeptide (GIP), and LH/human chorionic gonadotropin (hCG), expressed by AIMAH tissues to evaluate the role of ectopic receptors in the physiopathology of Cushing's syndrome.


METHODS
We used in vitro studies on cultured adrenal hyperplasia cells.


METHODS
The setting was a university research laboratory.


METHODS
AIMAH tissues (H1-H3) were removed from three patients previously screened for illegitimate receptors.


METHODS
The main outcome measures were steroidogenic and electrical activities of cultured adrenal hyperplasia cells.


RESULTS
In vitro studies showed that the corticotropic effect of 5-HT was mediated by ectopic 5-HT7 receptors in H1 and H2. GIP and hCG stimulated cortisol production via activation of cAMP-dependent protein kinase A in H2. On the contrary, the protein kinase A inhibitor H-89 did not affect hCG-induced cortisol production in H3. Activation of 5-HT7 or GIP receptors enhanced T-type calcium current in H1 or H2 and H3, respectively. In addition, GIP reduced the amplitude of transient and sustained potassium currents in H2. Conversely, hCG did not modify T-type calcium current in H3.


CONCLUSIONS
These data show that, besides their coupling to the cAMP pathway, illegitimate adrenal receptors can activate additional transduction mechanisms, including modulation of membrane channels.
Louiset
Estelle
E
Institut National de la Santé et de la Recherche Médicale (INSERM) Unite 413, Hospital of Boisguillaume, Centre Hospitalier Universitaire of Rouen, 76031 Rouen Cedex, France. herve.lefebvre@chu-rouen.fr
Contesse
Vincent
V
Groussin
Lionel
L
Cartier
Dorthe
D
Duparc
Céline
C
Barrande
Gaëlle
G
Bertherat
Jérôme
J
Vaudry
Hubert
H
Lefebvre
Hervé
H
D000262:Adenylyl Cyclases / Q000378:metabolism; D000311:Adrenal Glands / Q000378:metabolism* / Q000473:pathology*; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000328:Adult; D002478:Cells, Cultured; D003480:Cushing Syndrome / Q000209:etiology* / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism* / Q000502:physiology; D005260:Female; D015870:Gene Expression; D006801:Humans; D006965:Hyperplasia; D066298:In Vitro Techniques; D007473:Ion Channels / Q000378:metabolism*; D008875:Middle Aged; D011964:Receptors, Gastrointestinal Hormone / Q000378:metabolism; D011974:Receptors, LH / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
D007473:Ion Channels; D011964:Receptors, Gastrointestinal Hormone; D011974:Receptors, LH; D011985:Receptors, Serotonin; C104425:serotonin 7 receptor; D000324:Adrenocorticotropic Hormone; C041086:gastric inhibitory polypeptide receptor; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases