title: QRFP induces aldosterone production via PKC and T-type calcium channel-mediated pathways in human adrenocortical cells: evidence for a novel role of GPR103.
abstract: Hormonal regulation of adrenal function occurs primarily through activation of GPCRs. GPCRs are central to many of the body's endocrine and neurotransmitter pathways. Recently, it was shown that activation of GPR103 by its ligand QRFP induced feeding, locomotor activity, and metabolic rate, and QRFP is bioactive in adipose tissue of obese individuals. Given that the adrenal gland is a pivotal organ for energy balance and homeostasis, we hypothesized that GPR103 and QRFP are involved in steroidogenic responses. Using qRT-PCR and immunohistochemistry, we mapped both GPR103 and QRFP in human fetal and adult adrenal gland as well as rat adrenals. Both were primarily localized in the adrenal cortex but not in the medulla. Activation of GPR103 in human adrenocortical H295R cells led to a decrease in forskolin-increased cAMP and an increase of intracellular Ca(2+) levels. In addition, treatment of H295R cells with QRFP induced aldosterone and cortisol secretion as measured by ELISA. These increases were accompanied by increased expression and activity of StAR, CYB11B1, and CYP11B2 as assessed by qRT-PCR and luciferase reporter assay, respectively. Using specific inhibitors, we also demonstrated that aldosterone induction involves MAPK, PKC, and/or T-type Ca(2+) channel-dependent pathways. These novel data demonstrate that QRFP induces adrenal steroidogenesis in vitro by regulating key steroidogenic enzymes involving MAPK/PKC and Ca(2+) signaling pathways.
authors: Division of Metabolic and Vascular Health, Warwick Medical School, University of Warwick, Coventry United Kingdom;
authors: Manjunath
authors: M
authors: Ramanjaneya
authors: Emmanouil
authors: E
authors: Karteris
authors: Jing
authors: J
authors: Chen
authors: Marcin
authors: M
authors: Rucinski
authors: Agnieszka
authors: A
authors: Ziolkowska
authors: Naima
authors: N
authors: Ahmed
authors: Sonja
authors: S
authors: Kagerer
authors: Olaf
authors: O
authors: Jöhren
authors: Hendrik
authors: H
authors: Lehnert
authors: Ludwik K
authors: LK
authors: Malendowicz
authors: Harpal S
authors: HS
authors: Randeva
mesh_terms: D000302:Adrenal Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000328:Adult; D000450:Aldosterone / Q000096:biosynthesis*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020747:Calcium Channels, T-Type / Q000187:drug effects / Q000378:metabolism*; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D020747:Calcium Channels, T-Type; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; C511787:QRFP peptide; C476582:QRFPR protein, human; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; D000450:Aldosterone; D000242:Cyclic AMP; D011493:Protein Kinase C; D002118:Calcium; D006854:Hydrocortisone
keywords: QRFP; adrenal cortex; aldosterone