G-protein-coupled receptors in aldosterone-producing adenomas: a potential cause of hyperaldosteronism

The source of aldosterone in 30–40% of patients with primary hyperaldosteronism (PA) is unilateral aldosterone-producing adenoma (APA). The mechanisms causing elevated aldosterone production in APA are unknown. Herein, we examined the expression of G-protein-coupled receptors (GPCRs) in APA and demonstrated that when compared with normal adrenals, there is a general elevation of certain GPCR in many APA and/or ectopic expression of GPCR in others. RNA samples from normal adrenals (n = 5), APAs (n = 10), and cortisol-producing adenomas (CPAs; n = 13) were used on 15 genomic expression arrays, each of which included 223 GPCR transcripts presented in at least 1 out of 15 of the independent microarrays. The array results were confirmed using real-time RT-PCR (qPCR). Four GPCR transcripts exhibited a statistically significant increase that was greater than threefold when compared with normal adrenals, suggesting a general increase in expression when compared with normal adrenal glands. Four GPCR transcripts exhibited a > 15-fold increase of expression in one or more of the APA samples when compared with normal adrenals. qPCR analysis confirmed array data and found the receptors with the highest fold increase in APA expression to be LH receptor, serotonin receptor 4, GnRH receptor, glutamate receptor metabotropic 3, endothelin receptor type B-like protein, and ACTH receptor. There are also sporadic increased expressions of these genes in the CPAs. Together, these findings suggest a potential role of altered GPCR expression in many cases of PA and provide candidate GPCR for further study.

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G-protein-coupled-receptor activation of the smooth muscle calponin gene

Biochemical Journal ◽

10.1042/bj3570587 ◽

2001 ◽

Vol 357 (2) ◽

pp. 587-592 ◽

Cited By ~ 9

Author(s):

Nickolai O. DULIN ◽

Sergei N. ORLOV ◽

Chad M. KITCHEN ◽

Tatyana A. VOYNO-YASENETSKAYA ◽

Joseph M. MIANO

Keyword(s):

Smooth Muscle ◽

Protein Kinase ◽

G Protein ◽

Transcriptional Activation ◽

Fold Increase ◽

Receptor Activation ◽

G Protein Coupled Receptors ◽

Mitogen Activated Protein Kinase ◽

G Protein Coupled

A hallmark of cultured smooth muscle cells (SMCs) is the rapid down-regulation of several lineage-restricted genes that define their in vivo differentiated phenotype. Identifying factors that maintain an SMC differentiated phenotype has important implications in understanding the molecular underpinnings governing SMC differentiation and their subversion to an altered phenotype in various disease settings. Here, we show that several G-protein coupled receptors [α-thrombin, lysophosphatidic acid and angiotensin II (AII)] increase the expression of smooth muscle calponin (SM-Calp) in rat and human SMC. The increase in SM-Calp protein appears to be selective for G-protein-coupled receptors as epidermal growth factor was without effect. Studies using AII showed a 30-fold increase in SM-Calp protein, which was dose- and time-dependent and mediated by the angiotensin receptor-1 (AT1 receptor). The increase in SM-Calp protein with AII was attributable to transcriptional activation of SM-Calp based on increases in steady-state SM-Calp mRNA, increases in SM-Calp promoter activity and complete abrogation of protein induction with actinomycin D. To examine the potential role of extracellular signal-regulated kinase (Erk1/2), protein kinase B, p38 mitogen-activated protein kinase and protein kinase C in AII-induced SM-Calp, inhibitors to each of the signalling pathways were used. None of these signalling molecules appears to be crucial for AII-induced SM-Calp expression, although Erk1/2 may be partially involved. These results identify SM-Calp as a target of AII-mediated signalling, and suggest that the SMC response to AII may incorporate a novel activity of SM-Calp.

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Hematopoietic progenitor kinase 1 (HPK1) negatively regulates prostaglandin E2–induced fos gene transcription

Blood ◽

10.1182/blood-2002-07-2316 ◽

2003 ◽

Vol 101 (9) ◽

pp. 3687-3689 ◽

Cited By ~ 19

Author(s):

Sansana Sawasdikosol ◽

Kristin M. Russo ◽

Steven J. Burakoff

Keyword(s):

Prostaglandin E2 ◽

G Protein ◽

Gene Transcription ◽

Ectopic Expression ◽

G Protein Coupled Receptors ◽

Negative Regulator ◽

Critical Signal ◽

Negative Regulatory Pathway ◽

Expression Studies ◽

G Protein Coupled

Prostaglandin E2 (PGE2) is the predominant eicosanoid product released by macrophages at the site of inflammation. Binding of PGE2 to its cognate 7 transmembrane-spanning G protein–coupled receptors (GPCRs) activates signaling pathways, leading to the synthesis of the Fos transcription factor. Because the Ste20 serine/threonine protein kinase (S/TPK) is a critical signal transducer for the G protein–coupled pheromone receptor in Saccharomyces cerevisiae, we postulated that the PGE2 GPCRs may activate one of the Ste20 mammalian orthologs. We demonstrate here that the catalytic activity of a hematopoietic cell–restricted, Ste20-related S/TPK, HPK1, is positively regulated by exposure to physiological concentrations of PGE2. Furthermore, ectopic expression studies implicated HPK1 as a negative regulator of PGE2-induced transcription of the fos gene. Our data suggest that PGE2-induced activation of HPK1 may represent a novel negative regulatory pathway capable of modulating PGE2-mediated gene transcription.

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Structure-Based Scaffold Repurposing for G Protein-Coupled Receptors: Transformation of Adenosine Derivatives into 5HT2B/5HT2C Serotonin Receptor Antagonists

Journal of Medicinal Chemistry ◽

10.1021/acs.jmedchem.6b01183 ◽

2016 ◽

Vol 59 (24) ◽

pp. 11006-11026 ◽

Cited By ~ 9

Author(s):

Dilip K. Tosh ◽

Antonella Ciancetta ◽

Eugene Warnick ◽

Steven Crane ◽

Zhan-Guo Gao ◽

...

Keyword(s):

G Protein ◽

Serotonin Receptor ◽

G Protein Coupled Receptors ◽

Receptor Antagonists ◽

Serotonin Receptor Antagonists ◽

Adenosine Derivatives ◽

G Protein Coupled

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Identification of Ciliary Localization Sequences within the Third Intracellular Loop of G Protein-coupled Receptors

Molecular Biology of the Cell ◽

10.1091/mbc.e07-09-0942 ◽

2008 ◽

Vol 19 (4) ◽

pp. 1540-1547 ◽

Cited By ~ 222

Author(s):

Nicolas F. Berbari ◽

Andrew D. Johnson ◽

Jacqueline S. Lewis ◽

Candice C. Askwith ◽

Kirk Mykytyn

Keyword(s):

G Protein ◽

Serotonin Receptor ◽

Primary Cilia ◽

Consensus Sequence ◽

G Protein Coupled Receptors ◽

Intracellular Loop ◽

The Third ◽

Third Intracellular Loop ◽

G Protein Coupled ◽

Ciliary Localization

Primary cilia are sensory organelles present on most mammalian cells. The functions of cilia are defined by the signaling proteins localized to the ciliary membrane. Certain G protein–coupled receptors (GPCRs), including somatostatin receptor 3 (Sstr3) and serotonin receptor 6 (Htr6), localize to cilia. As Sstr3 and Htr6 are the only somatostatin and serotonin receptor subtypes that localize to cilia, we hypothesized they contain ciliary localization sequences. To test this hypothesis we expressed chimeric receptors containing fragments of Sstr3 and Htr6 in the nonciliary receptors Sstr5 and Htr7, respectively, in ciliated cells. We found the third intracellular loop of Sstr3 or Htr6 is sufficient for ciliary localization. Comparison of these loops revealed a loose consensus sequence. To determine whether this consensus sequence predicts ciliary localization of other GPCRs, we compared it with the third intracellular loop of all human GPCRs. We identified the consensus sequence in melanin-concentrating hormone receptor 1 (Mchr1) and confirmed Mchr1 localizes to primary cilia in vitro and in vivo. Thus, we have identified a putative GPCR ciliary localization sequence and used this sequence to identify a novel ciliary GPCR. As Mchr1 mediates feeding behavior and metabolism, our results implicate ciliary signaling in the regulation of body weight.

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