Edited by Henrik G. Dohlman G protein-coupled receptors (GPCRs) play critical roles in regulating processes such as cellular homeostasis, responses to stimuli, and cell signaling. Accordingly, GPCRs have long served as extraordinarily successful drug targets. It is therefore not surprising that the discovery in the mid-1990s of a family of proteins that regulate processes downstream of GPCRs generated great excitement in the field. This finding enhanced the understanding of these critical signaling pathways and provided potentially new targets for pharmacological intervention. These regulators of G-protein signaling (RGS) proteins were viewed by many as nodes downstream of GPCRs that could be targeted with small molecules to tune signaling processes. In this review, we provide a brief overview of the discovery of RGS proteins and of the gradual and continuing discovery of their roles in disease states, focusing particularly on cancer and neurological disorders. We also discuss high-throughput screening efforts that have led to the discovery first of peptide-based and then of small-molecule inhibitors targeting a subset of the RGS proteins. We explore the unique mechanisms of RGS inhibition these chemical tools have revealed and highlight the most up-to-date studies using these tools in animal experiments. Finally, we discuss the future opportunities in the field, as there are clearly more avenues left to be explored and potentials to be realized.
Exposure to environmental contaminants can result in a myriad of conditions including developmental disorders, pulmonary conditions, and neurological pathologies. Literature precedent and new, emerging data, demonstrates specific GPCRs can be activated by some classes of environmental contaminants, including PCBs, pesticides, chloropropanols, and others. When interrogating GPCR’s with small‐molecule based screens, the traditional paradigm is to test hundreds of thousands of compounds against a single target. In recent literature, an open‐source method “PRESTO‐TANGO” (Parallel Receptor‐ome Expression and Screening via Transcriptional Output – TANGO) has been described as a feasible approach to simultaneously screen the entire druggable human GPCR‐ome against a smaller collection of compounds via a G protein‐independent β‐arrestin recruitment assay. In this work, we have adopted a similar approach to the PRESTO‐TANGO methodology, enabling us to screen activity of a number of environmental contaminates against the known druggable GPCR‐ome of 314 GPCRs. From our initial screen, we identified several potential ligand‐receptor interactions. Secondary dose response experiments uncovered what we believe to be a novel ligand‐receptor relationship between PCBs and the Sphingosine‐1‐phoshpate receptor (S1PR) family. Experiments to validate the relationship between the PCBs and S1PR family, as well as investigate the relevant signaling cascades impacted are currently underway. Ultimately, this work utilizes a modified form of the PRESTO‐TANGO assay as a novel screening platform to elucidate bioactivity of environmental contaminants. Support or Funding Information This work was supported by the University of Iowa Environmental Health Science Research Center (NIEHS P30 ES05605 D.L.R)
Regulators of G‐protein signaling (RGS) is a family of approximately 30 proteins that bind to the alpha subunits of G‐proteins (Galpha) and accelerate their GTP hydrolysis rates. This deactivates the G‐protein and terminates G‐Protein Coupled Receptors (GPCRs) signaling. RGS proteins, therefore, play important roles in regulating GPCR signaling and most members are implicated in human diseases such as hypertension, depression, and others. Regulator of G‐protein Signaling 2 (RGS2) is a regulator of angiotensin‐II receptor signaling and a modulator of oxytocin receptor signaling as well. More importantly, RGS2 was reported to be over expressed in the majority of solid breast cancers and in metastatic prostate cancer. For this reason, we sought to develop RGS2 inhibitors as potential chemotherapeutic agents. We utilized structure‐based drug design approaches to develop inhibitors of RGS2‐Galpha‐q interactions. Available structures of the RGS2‐Galpha complex were used to extract a pharmacophore model for searching of commercially available chemical databases. The identified hits were docked to different RGS structures to screen for compounds with the highest binding potential and most selectivity towards RGS2. We report the first group of inhibitors of RGS2‐Galpha‐q interactions developed through rational drug design that interfered with RGS2 signaling in cell‐based assays. In addition, inhibitor AJ‐3 inhibited the growth of MCF‐7 breast cancer cells in cell culture assays, which suggests that RGS2 inhibitors may have a potential to be a new class of chemotherapeutic agents.
ID 28830 Poster Board 56From intentional production and unintended byproducts of industrialization, large amounts of anthropogenic chemicals have been produced and amassed in the environment. These environmental contaminants can disrupt physiological equilibria and cause diverse harm to human health, such as developmental disorders, immunological-mediated diseases, and neurological pathologies. Past literature and emerging data show that certain environmental contaminants can activate specific GPCRs. However, studies focus on specific contaminant-receptor pairs in detail, leaving the vast majority of the GPCR landscape unexplored. As GPCRs act as signaling nodes in many physiological processes, we hypothesized that interrogating the activity of a contaminant against the GPCRome could be used to assess biological impact while simultaneously providing insight into potential mechanisms of pathology. This work applies traditional pharmacology and drug discovery practices toward toxicology efforts. Utilizing the opensource platform (PRESTO-Tango), we developed a screening methodology capable of investigating the activity of contaminants against 314 non-olfactory GPCRs amendable to high-throughput. From our initial screen of eight compounds, we identified several interactions between polychlorinated biphenyls (PCBs) and GPCRs, including both characterized and orphan receptors. Most interesting are the relationships uncovered between specific PCB congeners (PCB95 and PCB52) and receptor isoforms involved in sphingosine-1-phosphate and melatonin signaling pathways (S1PR4 and MTb). To our knowledge, this is the first report of these interactions, highlighting the utility of our approach to quickly assess the biological impact and pathology of a contaminant at the receptor level. Additionally, while detailed pharmacological experiments are underway, these findings could potentially support the involvement of sphingosine and melatonin signaling interplay in pathologies beyond the contaminant(s) alone.
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