Small molecule modifiers of circadian clocks
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Cellular and Molecular Life Sciences
REVIEW
Small molecule modifiers of circadian clocks Zheng Chen • Seung-Hee Yoo • Joseph S. Takahashi
Received: 18 September 2012 / Revised: 26 October 2012 / Accepted: 29 October 2012 / Published online: 16 November 2012 Ó Springer Basel 2012
Abstract Circadian clocks orchestrate 24-h oscillations of essential physiological and behavioral processes in response to daily environmental changes. These clocks are remarkably precise under constant conditions yet highly responsive to resetting signals. With the molecular composition of the core oscillator largely established, recent research has increasingly focused on clock-modifying mechanisms/molecules. In particular, small molecule modifiers, intrinsic or extrinsic, are emerging as powerful tools for understanding basic clock biology as well as developing putative therapeutic agents for clock-associated diseases. In this review, we will focus on synthetic compounds capable of modifying the period, phase, or amplitude of circadian clocks, with particular emphasis on the mammalian clock. We will discuss the potential of exploiting these small molecule modifiers in both basic and translational research.
Abbreviations ARNT Aryl hydrocarbon receptor nuclear translocator bHLH PAS Basic helix–loop–helix PER-ARNT-SIM BMAL1 Brain and muscle aryl hydrocarbon receptor nuclear translocator (ARNT)-like CEM Clock-enhancing molecule CLOCK Circadian locomotor output cycles kaput CREB cAMP response element-binding protein CRY Cryptochrome FASPS Familial advanced sleep phase syndrome HIF Hypoxia-inducible factor NPAS2 Neuronal PAS domain protein 2 PER Period ROR Retinoid acid receptor-related orphan receptor SCN Suprachiasmatic nuclei
Keywords Metabolites Synthetic compounds Period Phase Amplitude Clock-associated diseases Chronotherapy
Introduction
Z. Chen (&) Department of Biochemistry and Molecular Biology, University of Texas Health Science Center at Houston, 6431 Fannin St., Houston, TX 77030, USA e-mail: [email protected] S.-H. Yoo J. S. Takahashi Department of Neuroscience, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA J. S. Takahashi (&) Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA e-mail: [email protected]
To cope with daily environmental changes due to the earth’s rotation, virtually all living organisms have evolved an intrinsic time-keeping mechanism called the circadian clock [1–8]. The fundamental unit of animal clocks is a cellautonomous oscillator consisting of transcriptional-translational feedback loops [9, 10]. In the primary feedback loop of the mammalian oscillator, heterodimeric transcription factors CLOCK/BMAL1 and NPAS2/BMAL1 activate expression of the Period1/2 and Cryptochrome1/2 genes. The resulting protein products, PER1/2 and CRY1/2, translocate to the nucleus where they inhibit CLOCK/ BMAL1 and NPAS2/BMAL1 and repress their own expression. Various transcriptional a
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