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

Randeva HS. QRFP induces aldosterone production via PKC and T-type calcium channel-mediated pathways in human adrenocortical cells: evidence for a novel role of GPR103. Am J Physiol Endocrinol Metab 305: E1049 -E1058, 2013. First published August 20, 2013; doi:10.1152/ajpendo.00191.2013.-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 2ϩ 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 2ϩ channel-dependent pathways. These novel data demonstrate that QRFP induces adrenal steroidogenesis in vitro by regulating key steroidogenic enzymes involving MAPK/PKC and Ca 2ϩ signaling pathways. adrenal cortex; QRFP; aldosterone THE ADRENAL GLAND and its associated hormones developed as protection from immediate stress or injury and against prolonged periods of food and water deprivation. The adrenal cortex and medulla, despite being adjacent to each other, are separate organs in terms of their tissue origin (5). Adrenal steroid hormones include cortisol as the major glucocorticoid and stress-adapting hormone and aldosterone, which is involved in sodium ion uptake and modulates blood pressure and adrenal androgens; in certain conditions they can act as precursors for testosterone (8). Hormonal regulation of adrenal function occurs primarily through activation of G proteincoupled receptors (GPCRs) (38). GPCRs are central to many of the body's endocrine and neurotransmitter pathways, and their dysfunction contributes to some of the most prevalent human diseases (12). In a recent study, gonadotropin-releasing hormone receptor (GnRHR), latrophilin 3 receptor, G proteincoupled receptor 37, angiotensin II receptor type 2, latrophilin 2 receptor, and melanocortin receptor were shown to be expressed at significantly higher levels in fetal compared with adult adrenals (38). These findings not only implicate further GPCRs in adrenal function but suggest that they may play different roles...

RFamide Peptides 43RFa and 26RFa Both Promote Survival of Pancreatic β-Cells and Human Pancreatic Islets but Exert Opposite Effects on Insulin Secretion

“…In humans and rodents, 43RFa, 26RFa, and GPR103 are mainly expressed in brain, particularly in the hypothalamus (8), as well as in peripheral tissues, including the eye, testis, thyroid, adipose tissue, and macrophages (6,(9)(10)(11). 43RFa and 26RFa have been implicated in many physiological functions, including stimulation of food intake (5,(12)(13)(14)(15)(16)(17), regulation of gonadotropic axis (18,19), aldosterone secretion (7,20), bone formation (21), adipogenesis and inflammation (10,11), blood pressure (12), and prostate cancer differentiation and migration (22).…”

Regulation of the expression of corticotropin-releasing factor gene by pyroglutamylated RFamide peptide in rat hypothalamic 4B cells

“…However, it is unclear whether endogenous QRFP stimulates the HPA axis in vivo. Both Gpr103 and QRFP are primarily localized in human and rat adrenal cortex [7,9]. QRFP stimulates cortisol secretion as well as induction of key steroidogenic enzymes in human adrenocortical cells [7].…”

“…QRFP has orexigenic effects in rodents [1][2][3][4][5]. QRFP also regulates behavioral arousal, blood pressure, locomotor activity, and aldosterone and insulin secretion [2,6,7]. QRFP acts via a specific receptor, Gpr103, which belongs to the G proteincoupled receptor superfamily [2,8].…”

Positive selection effects on the biochemical properties of mammal pyroglutamylated RFamide peptide receptor (QRFPR)

“…Previous results suggested that QRFPR is coupled to a Gi/0 and/or to a Gq protein (Fukusumi et al 2003). Furthermore, it has been reported that 26RFa/QRFP enhances corticosteroid secretion in human adrenocortical cells by regulating key steroidogenic enzymes involving MAPK/PKC (mitogen-activated protein kinase/protein kinase C) and Ca 2+ (calcium ions) signaling pathways via QRFPR (Ramanjaneya et al 2013).…”