How to fix a broken clock Analyne M. Schroeder, Christopher S. Colwell  Trends in Pharmacological Sciences  Volume 34, Issue 11, Pages 605-619 (November 2013) DOI: 10.1016/j.tips.2013.09.002 Copyright © 2013 Elsevier Ltd Terms and Conditions

Figure 1 The molecular clock. The molecular feedback loop is at the core of circadian rhythm generation and drives approximately 24h oscillations in core clock protein expression. The loop is composed of a positive arm (CLOCK and BMAL1) that bind to E-box consensus sequences driving the expression of PER and CRY, components of the negative arm of the loop. PER and CRY inhibit the ability of CLOCK and BMAL1 to bind onto DNA, thereby leading to a gradual decline of PER and CRY levels, allowing CLOCK and BMAL1 to once again restart the positive drive of the loop. Post-translational modifications by CK1δ,ɛ, or additional loops (REV-ERB and ROR regulation of Bmal1 expression) reinforce and fine-tune the clock. Many of these circadian clock genes drive the rhythmic expression of other output genes or clock-controlled genes (CCGs) that are involved in a variety of cellular processes. Abbreviations: +/−, positive and negative arms; BMAL1, brain and muscle ARNT-like 1/Arntl; Clock, Circadian locomotor Output Cycles Kaput; CK1δ,ɛ, casein kinases 1δ,ɛ; CRY, cryptochrome; PER, period; Nr1d1/2, nuclear receptor subfamily 1, group D, members 1,2 (REV-ERBα/β); ROR, retinoid acid receptor (RAR)-related orphan receptor. Trends in Pharmacological Sciences 2013 34, 605-619DOI: (10.1016/j.tips.2013.09.002) Copyright © 2013 Elsevier Ltd Terms and Conditions

Figure 2 Melatonin signaling and modulation of the molecular clock. Melatonin is the most-studied pharmacological agent that modulates and benefits the circadian system. Melatonin interactions with the melatonin MT1 and MT2 G-αi and G-αq protein-coupled receptors leads to the inhibition of adenylate cyclase (AC) and phospholipase C (PLC) and downregulation of protein kinase A (PKA)/protein kinase C (PKC) signaling, altering ion-channel function and changes in circadian-related transcription. Melatonin also binds to the enzyme quinone reductase 2 (NQO2) and modulates the function of nuclear receptors, although the physiological significance of this binding is not yet clear. Trends in Pharmacological Sciences 2013 34, 605-619DOI: (10.1016/j.tips.2013.09.002) Copyright © 2013 Elsevier Ltd Terms and Conditions

Figure 3 Drug targets of the molecular clock. Various pathways that modulate the core molecular feedback loop can be targeted by pharmacological agents leading to changes in the amplitude, phase, and period of molecular oscillations. Results from ongoing high-throughput screens will expand potential druggable pathways that could one day lead to medications able to modulate the circadian system predictably. Abbreviations: AMPK, AMP-activated protein kinase; CREB, cAMP responsive element binding protein 1; GSK-3β, glycogen synthase kinase 3β; for other abbreviations see Figure 1 legend. Trends in Pharmacological Sciences 2013 34, 605-619DOI: (10.1016/j.tips.2013.09.002) Copyright © 2013 Elsevier Ltd Terms and Conditions