Interactions of the circadian CLOCK system and the HPA axis

Abstract

Organisms have developed concurrent behavioral and physiological adaptations to the strong influence of day/night cycles, as well as to unforeseen, random stress stimuli. These circadian and stress-related responses are achieved by two highly conserved and interrelated regulatory networks, the circadian CLOCK and stress systems, which respectively consist of oscillating molecular pacemakers, the Clock/Bmal1 transcription factors, and the hypothalamic-pituitary-adrenal (HPA) axis and its end-effector, the glucocorticoid receptor. These systems communicate with one another at different signaling levels and dysregulation of either system can lead to development of pathologic conditions. In this review, we summarize the mutual physiologic interactions between the circadian CLOCK system and the HPA axis, and discuss their clinical implications.

Figure 1

The circadian CLOCK system is regulated by a self-oscillating transcriptional loop. The C heterodimer Clock/Bmal1 binds to E-box elements located in the promoter region and stimulates expression of essential clock transcription factors Pers and Crys (i), which in turn repress the transcriptional activity of the CLOCK/BMAL1 heterodimer by inhibiting its binding to the E-box response elements located in their own promoters through formation of a complex with and subsequent phosphorylation by the caseine kinase 1ε and δ (ii). Clock/Bmal1 also stimulates expression of other CLOCK-related proteins, such as Rev-erbα, RORα, Dec1, Dec2 and Dbp (iii), which create an auxiliary loop that helps stabilize the main regulatory loop. These clock transcription factors control numerous “downstream” CLOCK-responsive genes to influence a variety of biologic activities (iv). Bmal1: brain-muscle-arnt-like protein 1, Clock: circadian locomotor output cycle kaput, Crys: cryptochromes, Csnk1ε/δ: caseine kinase 1ε/δ, P: phosphate residue on the phsphorylated molecules, Pers: periods, RORγ: retinoic acid receptor-related orphan nuclear receptor γ.

Figure 2

The circadian CLOCK system and the HPA axis influence each other’s activity at multiple levels. The central CLOCK under the regulation of the light input controls the HPA axis and produces regular diurnal secretion of glucocorticoid hormones from the adrenal glands, while the peripheral CLOCKs, which is located in the adrenal glands and other components of the HPA axis and are regulated by the central CLOCK through the sympathetic nervous system, also contribute to the rhythmic glucocorticoid secretion from these organs. Secreted glucocorticoids in turn reset and phase-delay circadian rhythm of the peripheral CLOCKs by stimulating the expression of several CLOCK-related genes; this is especially important for temporal adjustment of body’s activity against stress. The peripheral CLOCKs also regulate glucocorticoid effect in local tissues through interaction between Clock/Bmal1 and GR, providing a local counter regulatory feedback loop to the effect of central CLOCK on the HPA axis. ACTH: adrenocorticotropic hormone, AVP: arginine vasopressin, CRH: corticotropin-releasing hormone, PVN: paraventricular nucleus, SCN: Suprachiasmatic nucleus.

Figure 3

Clock/Bmal1 suppresses GR-induced transcriptional activity through acetylation. (a) Clock physically interacts with the ligand-binding domain of the GR through the domain enclosed in it s C-terminal part and suppresses GR-induced transcriptional activity by acetylating via its intrinsic HAT activity a lysine cluster located in the hinge region of the GR, through which (b) Clock reduces affinity of GR to its cognate DNA sequences GREs. A: acetylation, Bmal1: brain-muscle-arnt-like protein 1, DBD: DNA-binding domain, GR: glucocorticoid receptor, GRE: glucocorticoid response element, HR: hinge region, K: lysine residue, LBD: ligand-binding domain, NTD: N-terminal domain C: A heuristic model of the physiologic implications of this study. Modified from .

Figure 4

A heuristic scheme of the circadian secretion of cortisol in non-stressed and chronically stressed humans (top left panel) and their responses to midnight dexamethasone administration (top right panel), the corresponding circadian changes of target tissue sensitivity to glucocorticoids (middle panel) and the mean target tissue sensitivity to glucocorticoids in the human population (bottom panel). It is obvious that even mild evening cortisol elevations, as those seen in chronically stressed individuals, will exert disproportionately increased glucocorticoid effects because of the natural circadian target tissue sensitivity increase at this time of the day. CS: Chronically stressed individuals, D: midnight dexamethasone administration, HS: hypersensitivity, N: normal sensitivity, NS: non-stressed individuals, R: resistance Modified from .

Figure I of Box-1

Central CLOCK synchronizes the peripheral CLOCKs and regulates peripheral organ activities via neural and humoral interactions. The central master CLOCK located in the SCN (core) obtains light/dark information from the retina through the retinohypothalamic track (RHT), and adjusts its circadian rhythm, while it indirectly projects several efferent neurons to transmit timing information to other parts of the brain and distant organs for synchronizing their peripheral CLOCKs and influencing their activities, such as secretion of pituitary hormones and melatonin, food intake, sleep and body temperature. The central master CLOCK employs the autonomic nervous system and humoral mediators for organ regulation. For simplicity, detailed anatomical structures for the sympathetic and parasympathetic nervous systems, such as nuclei located in the brain stem including the solitary nucleus and the ambiguous nucleus and the sympathetic and parasympathetic ganglia, are omitted. DMH: dorsomedial nucleus of hypothalamus, DMV: dorsal motor nucleus of vagus, MPO: medial preoptic region, PVN: paraventricular nucleus, RHT: retinohypothalamic tract, SCN: suprachiasmatic nucleus.