Expression of Serotonin₇Receptor and Coupling of Ectopic Receptors to Protein Kinase A and Ionic Currents in Adrenocorticotropin-Independent Macronodular Adrenal Hyperplasia Causing Cushing’s Syndrome

Abstract

These data show that, besides their coupling to the cAMP pathway, illegitimate adrenal receptors can activate additional transduction mechanisms, including modulation of membrane channels.

ACTH-Independent Hypercorticism in Adrenal Tumors and Adrenocortical Hyperplasia

“…52,53 The cultured AIMAH cells exhibit T-type Ca 2+ currents enhanced by 5-HT(10 -5 M) at -50 and -30 mV. 44 These data are consistent with the results in animal experiments, suggesting that the activation of adenylyl cyclase via 5-HT 4 receptors and the subsequent rise of intracellular Ca 2+ through T-type calcium channels stimulated the secretion of corticosteroid in adrenocortical cells. 54,55 Treatment with H-89, a protein kinase A (PKA) inhibitor, greatly reduced the spontaneous production of cortisol in the cell cultures and blocked the action of 5-HT cells in most patients.…”

“…41 All 5-HT receptors except 5-HT 3 are G-protein coupled receptors (GPCRs), and most of them are coupled with adenylyl cyclase. Both 5-HT and cisapride, a 5-HT 4 receptor agonist, stimulated cortisol production in vivo, 42 in cultured cells from adrenal hyperplasia 37,43,44 and adrenocortical carcinoma. 45 Patients with Cushing's syndrome treated with 5-HT 4 receptor agonists cisapride, 43,46-50 metoclopramide, 46,48 and zacopride demonstrated increased cortisol levels.…”

“…54,55 Treatment with H-89, a protein kinase A (PKA) inhibitor, greatly reduced the spontaneous production of cortisol in the cell cultures and blocked the action of 5-HT cells in most patients. 44 Clusters of steroidogenic cells demonstrated 5-HT and AVP-like (detailed in the next section) immunoreactivity, suggesting that these two factors may use paracrine or autocrine mechanisms to stimulate cortisol secretion. 43 In some cases, the corticotropic effect of 5-HT was mediated by ectopic 5-HT 7 receptors.…”

Cushing's syndrome secondary to ACTH-Independent macronodular adrenal hyperplasia

“…In the two of these patients with normal levels of this receptor, the molecular mechanism of the aberrant response remains unclear, and no differences in splice variants or in the cDNA sequence of the receptor were identified (58). More recently, the ectopic expression and function of 5HT 7 receptor was identified in a patient with serotoninresponsive AIMAH and Cushing's syndrome (60).…”

“…After the first description of combined aberrant LH and serotonin 5-HT 4 receptors in AIMAH, several patients were identified with an increased cortisol secretion after cisapride, metoclopramide or tegaserod stimulation (16,48,(56)(57)(58)(59)(60). In six patients with AIMAH and aberrant response to cisapride or metoclopramide, adrenal overexpression of 5HT 4 receptor was found in four patients.…”