The Role of Clock Genes in Pharmacology

Paschos, Georgios K.; Baggs, Julie E.; Hogenesch, John B.; FitzGerald, Garret A.

doi:10.1146/annurev.pharmtox.010909.105621

Cited by 86 publications

(72 citation statements)

References 180 publications

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supporting

confidence: 54%

“…In their review, Chen et al (15) discuss this aspect and highlight the potential of small-molecule modulators of the circadian system. These ideas extend ones previously reviewed in ARPT (16,17) and are an aspect of pharmacology and toxicology that relates to discoveries for which the 2017 Nobel Prize in Physiology or Medicine was awarded (for discoveries of molecular mechanisms that control the circadian rhythm).An additional environmental factor relates to an individual's microbiomes in various parts of the body. Much recent data have identified the role of microbiomes in aspects of physiology and pathophysiology.…”

mentioning

confidence: 58%

See 1 more Smart Citation

Introduction to the Theme “New Approaches for Studying Drug and Toxicant Action: Applications to Drug Discovery and Development”

Insel

Amara

Blaschke

et al. 2018

Annu. Rev. Pharmacol. Toxicol.

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The theme "New Approaches for Studying Drug and Toxicant Action: Applications to Drug Discovery and Development" links 13 articles in this volume of the Annual Review of Pharmacology and Toxicology (ARPT ). The engaging prefatory articles by Arthur Cho and Robert Lefkowitz set the stage for this theme and for the reviews that insightfully describe new approaches that advance research and discovery in pharmacology and toxicology. Examples include the progress being made in developing Organson-Chips/microphysiological systems and human induced pluripotent stem cell-derived cells to aid in understanding cell and tissue pharmacokinetics, action, and toxicity; the recognition of the importance of circadian rhythm, the microbiome, and epigenetics in drug and toxicant responses; and the application of results from new types of patient-derived information to create personalized/precision medicine, including therapeutics for pain, which may perhaps provide help in dealing with the opioid epidemic in the United States. Such new information energizes discovery efforts in pharmacology and toxicology that seek to improve the efficacy and safety of drugs in patients and to minimize the consequences of exposure to toxins. Applications to Drug Discovery and Development," complements and extends the themes of previous volumes ("Precision Medicine and Prediction in Pharmacology" and "New Methods and Novel Therapeutic Approaches in Pharmacology and Toxicology"). We believe that this theme will inform readers of findings that have and will continue to have an important impact on pharmacology and toxicology. Below, we highlight 13 articles for the current theme. The highly engaging prefatory articles by Arthur Cho (the previous Editor of ARPT; 1) and Robert Lefkowitz (2) demonstrate their originality in approaching scientific discovery, although in the case of Lefkowitz, this occurred in a rather serendipitous manner. His contributions have been widely recognized, including by the 2012 Nobel Prize in Chemistry. Of note, Lefkowitz's early contributions derive from the use of radioligand binding to identify adrenergic receptors, studies that complement the early work of Solomon Snyder, whose prefatory article appeared in Volume 57 of ARPT (3). Almost 50 years after being introduced and validated as a technique, radioligand binding remains useful for characterizing drug and hormone receptors and defining aspects of receptor biology, including the identification of allosteric modulators, an active area of research and discovery in academia and the drug industry (4, 5).Radioligand binding is a reductionist approach that complements assessments of drug and toxicant responses in physiologic systems, such as organ baths. Recent progress in efforts to create ex vivo models of tissues and organs have involved the use of tissue-derived cells and cell lines that can be assembled in a manner that mimics the in vivo setting. Such microphysiological systems can create Organs-on-Chips and provide novel ways to assess pharmacokinetics, pharm...

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supporting

confidence: 54%

mentioning

confidence: 58%

Introduction to the Theme “New Approaches for Studying Drug and Toxicant Action: Applications to Drug Discovery and Development”

Insel

Amara

Blaschke

et al. 2018

Annu. Rev. Pharmacol. Toxicol.

View full text Add to dashboard Cite

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“…As demonstrated in various microarray studies, genes important for gluconeogenesis, lipogenesis, and cholesterol synthesis are potential targets of clock proteins (5)(6)(7)(8). Therefore, for drug administration and drug design, it becomes critical to understand how the cycling of individual metabolic genes is regulated in a 24-h rhythm (9,10). E4BP4 (E4-binding protein 4), also called NFIL3, is a b-ZIP (basic leucine zipper) transcription factor initially identified as an IL-3-inducible factor in pro-B lymphocytes (11)(12)(13).…”

mentioning

confidence: 99%

Transcriptional Repressor E4-binding Protein 4 (E4BP4) Regulates Metabolic Hormone Fibroblast Growth Factor 21 (FGF21) during Circadian Cycles and Feeding

Tong

Muchnik

Chen

et al. 2010

Journal of Biological Chemistry

101

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Fibroblast growth factor 21 (FGF21) is a potent antidiabetic and triglyceride-lowering hormone whose hepatic expression is highly responsive to food intake. FGF21 induction in the adaptive response to fasting has been well studied, but the molecular mechanism responsible for feeding-induced repression remains unknown. In this study, we demonstrate a novel link between FGF21 and a key circadian output protein, E4BP4. Expression of Fgf21 displays a circadian rhythm, which peaks during the fasting phase and is anti-phase to E4bp4, which is elevated during feeding periods. E4BP4 strongly suppresses Fgf21 transcription by binding to a D-box element in the distal promoter region. Depletion of E4BP4 in synchronized Hepa1c1c-7 liver cells augments the amplitude of Fgf21 expression, and overexpression of E4BP4 represses FGF21 secretion from primary mouse hepatocytes. Mimicking feeding effects, insulin significantly increases E4BP4 expression and binding to the Fgf21 promoter through AKT activation. Thus, E4BP4 is a novel insulin-responsive repressor of FGF21 expression during circadian cycles and feeding.The mammalian circadian rhythm system plays a fundamental role in coordinating various physiological processes, which are manifested by a precise 24-h cycle and responsiveness to light or food cues (1-4). Recent genetic and biochemical studies of mammals, Drosophila, and bacteria have provided a general model of the circadian clock that is based on a transcriptional-translational feedback loop consisting of both positive and negative circadian clock proteins (1, 4). Besides controlling the core circadian oscillation loop, the clock proteins also actively participate in rhythmic expression of various output genes, which may account for the rhythmic activities in peripheral tissues (1, 3). As demonstrated in various microarray studies, genes important for gluconeogenesis, lipogenesis, and cholesterol synthesis are potential targets of clock proteins (5-8). Therefore, for drug administration and drug design, it becomes critical to understand how the cycling of individual metabolic genes is regulated in a 24-h rhythm (9, 10). E4BP4 (E4-binding protein 4), also called NFIL3, is a b-ZIP (basic leucine zipper) transcription factor initially identified as an IL-3-inducible factor in pro-B lymphocytes (11-13). The biological function of E4BP4 has been largely explored in the immune system, in which E4BP4 knock-out mice are defective in natural killer cell development and IgE class switch (14 -16). E4BP4 was first identified as a clock-controlled gene in mouse liver (17,18). Its mRNA and protein levels oscillate in a circadian fashion, which is anti-phase to DBP (D-site of albumin promoter-binding protein), another clock-controlled output gene (19). The mRNA of E4BP4 peaks at circadian time (CT) 2 0 and troughs at CT 12 (17,20). Although the role of E4BP4 in the mammalian circadian system is unclear, its homologue in Drosophila, vrille, serves as a key component of the core circadian network via a negative feedback loop (21-23). E...

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“…common diseases, including hypertension, diabetes, obesity, and cancer [1][2][3][4][5]. It is worth noting that drug efficacy and toxicity also change with time in a manner depending on the endogenous clock [6]. These lines of growing evidence support the potential value of developing drugs that target the circadian clock.…”

Section: The Scn Is the Center Of The Body Clockmentioning

confidence: 95%

G-protein-coupled receptor signaling through Gpr176, Gz, and RGS16 tunes time in the center of the circadian clock [Review]

et al. 2017

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Abstract. G-protein-coupled receptors (GPCRs) constitute an immensely important class of drug targets with diverse clinical applications. There are still more than 120 orphan GPCRs whose cognate ligands and physiological functions are not known. A set of circadian pacemaker neurons that governs daily rhythms in behavior and physiology resides in the suprachiasmatic nucleus (SCN) in the brain. Malfunction of the circadian clock has been linked to a multitude of diseases, such as sleeping disorders, obesity, diabetes, cardiovascular diseases, and cancer, which makes the clock an attractive target for drug development. Here, we review a recently identified role of Gpr176 in the SCN. Gpr176 is an SCN-enriched orphan GPCR that sets the pace of the circadian clock in the SCN. Even without known ligand, this orphan receptor has an agonist-independent basal activity to reduce cAMP signaling. A unique cAMP-repressing G-protein subclass Gz is required for the activity of Gpr176. We also provide an overview on the circadian regulation of G-protein signaling, with an emphasis on a role for the regulator of G-protein signaling 16 (RGS16). RGS16 is indispensable for the circadian regulation of cAMP in the SCN. Developing drugs that target the SCN remains an unfulfilled opportunity for the circadian pharmacology. This review argues for the potential impact of focusing on GPCRs in the SCN for the purpose of tuning the body clock.

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The Role of Clock Genes in Pharmacology

Cited by 86 publications

References 180 publications

Introduction to the Theme “New Approaches for Studying Drug and Toxicant Action: Applications to Drug Discovery and Development”

Introduction to the Theme “New Approaches for Studying Drug and Toxicant Action: Applications to Drug Discovery and Development”

Transcriptional Repressor E4-binding Protein 4 (E4BP4) Regulates Metabolic Hormone Fibroblast Growth Factor 21 (FGF21) during Circadian Cycles and Feeding

G-protein-coupled receptor signaling through Gpr176, Gz, and RGS16 tunes time in the center of the circadian clock [Review]

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