How to fix a broken clock

Abstract

Fortunate are those who rise out of bed to greet the morning light well rested with the energy and enthusiasm to drive a productive day. Others, however, depend on hypnotics for sleep and require stimulants to awaken lethargic bodies. Sleep/wake disruption is a common occurrence in healthy individuals throughout their lifespan and is also a comorbid condition to many diseases (neurodegenerative) and psychiatric disorders (depression and bipolar). There is growing concern that chronic disruption of the sleep/wake cycle contributes to more serious conditions including diabetes (type 2), cardiovascular disease, and cancer. A poorly functioning circadian system resulting in misalignments in the timing of clocks throughout the body may be at the root of the problem for many people. In this article we discuss environmental (light therapy) and lifestyle changes (scheduled meals, exercise, and sleep) as interventions to help fix a broken clock. We also discuss the challenges and potential for future development of pharmacological treatments to manipulate this key biological system.

Keywords: SCN; chrono-pharmacology; circadian; clock; melatonin; sleep.

Figure 1

The molecular clock. The molecular feedback loop is at the core of circadian rhythm generation and drives approximately 24 hr 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, which are 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 the 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 Casein Kinase 1 δ,ε (CK1 δ,ε) 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.

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 MT1 and MT2 G-α_i and G-α_q protein coupled receptors lead to the inhibition of adenylate cyclase (AC) and Phospholipase C (PLC) and down regulation of PKA/PKC signaling altering ion channel function and changes in circadian-related transcription. Melatonin also binds the enzyme quinone reductase 2 (NQO2) and modulates the function of nuclear receptors although the physiological significance of this binding is not yet clear.

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 drug-able pathways that could one day lead to medications able to predictably modulate the circadian system.