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

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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Receptor antagonists for gastrointestinal peptides

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1993.264.3.g399 ◽

1993 ◽

Vol 264 (3) ◽

pp. G399-G406

Author(s):

M. E. Presti ◽

J. D. Gardner

Keyword(s):

Receptor Antagonist ◽

G Protein ◽

Therapeutic Potential ◽

G Protein Coupled Receptors ◽

Gastrointestinal Function ◽

Receptor Antagonists ◽

Cholecystokinin Receptor ◽

Gastrointestinal Peptides ◽

Complex Regulation ◽

G Protein Coupled

Receptors for gastrointestinal peptides are all G protein-coupled receptors. Since the discovery that dibutyryl guanosine 3',5'-cyclic monophosphate was a cholecystokinin-receptor antagonist, a variety of receptor antagonists have been developed for a number of different gastrointestinal peptides. These antagonists have been useful in classifying receptors for gastrointestinal peptides and in elucidating complex regulation of gastrointestinal function. Some antagonists also have therapeutic potential. Based on the receptors with which they interact, gastrointestinal peptides can be grouped into families, and, in general, a given receptor antagonist is specific for a given family. This review covers the different families of gastrointestinal peptides and the major antagonists that exist for each family.

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Bradykinin B2 receptor antagonists: development and applications

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y95-106 ◽

1995 ◽

Vol 73 (7) ◽

pp. 787-790 ◽

Cited By ~ 9

Author(s):

John M. Stewart

Keyword(s):

G Protein ◽

Biomedical Research ◽

Clinical Applications ◽

G Protein Coupled Receptors ◽

Bradykinin Receptors ◽

Receptor Antagonists ◽

Bradykinin B2 Receptor ◽

Kinin Receptors ◽

Bradykinin Antagonists ◽

G Protein Coupled

Most physiological and pathophysiological responses to bradykinin are mediated by G-protein-coupled receptors designated B2 receptors. Discovery of antagonists for these receptors has brought about a revolution in research in the kinin field. The chemistry and development of antagonists for B2 kinin receptors are discussed. Uses of the antagonists in biomedical research and potential clinical applications are presented.Key words: bradykinin antagonists, bradykinin inflammation, bradykinin receptors.

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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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