Table 1. Communicating signals within the mammalian clock network.
Question mark indicates an undefined mechanism or target.
| Tissue | Signal | Mediator | Clock Target | Refs |
|---|---|---|---|---|
| Brain | Hypothalamic Neurotransmitters and Neuropeptides | Synaptic receptors, cAMP, PKA, CREB, ERK, PRDX, mTOR, Fos, Jun, DUSP4, NMDAR2C, GABAAR | Per, Cry | 36, 40 |
| Autonomic Nervous System | adrenergic, cholinergic receptors, MAPK, PKA | Per1 | 72 | |
| Sleep-Wake, Feed-Fast Cycles | Metabolic hormones, Nutrient flux, Coupled energy sensors (AMPK, SIRTs, PGClα), CO2, O2 | CLOCK:BMAL1, PER2, REV-ERBα | 22 | |
| Temperature Cycle | HSF1 | PER2, Per2 | 74, 75 | |
| Pituitary Gland | Vasopressin | AVPR1–3, CREB | Per1–2 | 66 |
| Pineal Gland | Melatonin | PKC | Per1–2 | 66 |
| Thyroid | Thyroxine; Triiodothyronine | Thyroid hormone receptor | ? | 66 |
| Adrenal Gland | Corticosterone | Glucocorticoid Receptor | CRY1–2, CLOCK, Clock gene GREs | 66 |
| Aldosterone | Mineralocorticoid receptor | Clock gene GREs | 66 | |
| Lung | O2 | HIF1α | CRY1, PER2, BMAL1 | 25 |
| CO2 | ? | ? | 76, 77 | |
| Adipose | Leptin | Leptin receptor | ? | 105, 106 |
| Adiponectin | AdipoR1–2 | ? | 82 | |
| Liver | FGF21 | β-Klotho | ? | 87 |
| Angptl8 | PirB, NF-κB, p38, Akt | Per1 | 83 | |
| IGF-1 | GSK-3β | Bmal1 | 99 | |
| RBP4 | ? | ? | 86 | |
| Skeletal Muscle | IL-6, IL-8, MCP-1 | ? | ? | 65 |
| Pancreas | Insulin | PTEN, mTORC1, Akt, miR24, 29, 30 | BMAL1 phosphorylation, PER, Per | 89, 48 |
| Glucagon | adenylate cyclase | ? | 48, 94 | |
| Somatostatin | SSTR2–3 | ? | 94 | |
| GLP-1 | GLP1R | ? | 94 | |
| GI Tract | Oxyntomodulin | Glucagon Receptor, CREB | Per | 85 |
| Ghrelin | GHSR | ? | 84 |
cAMP - cyclic adenosine monophosphate; PKA - protein kinase A; CREB - cAMP response element-binding protein; ERK - extracellular signal-regulated kinase; PRDX - peroxiredoxin; mTOR - mammalian target of rapamycin; DUSP4 - dual specificity protein phosphatase 4; N-methyl-D-aspartate receptor 2C; gamma-aminobutyric acid A receptor; Per - period; Cry - cryptochrome; MAPK - mitogen-activated protein kinase; AMPK - 5’ adenosine monophosphate-activated kinase; SIRT - sirtuin; PGC1α - peroxisome proliferator-activated receptor gamma coactivator 1-alpha; CLOCK - circadian locomotor output cycles kaput; BMAL1 - brain and muscle ARNT-Like 1; REV-ERBα - nuclear receptor subfamily 1, group D, member 1; HSF1 - heat shock factor 1; MRTF - myocardin-related transcription factor; PER2 - period 2; AVPR - arginine vasopressin receptor; PKC - protein kinase C; GRE - glucocorticoid response element; HIF1α - hypoxia-inducible factor 1-alpha; CRY1 - cryptochrome 1; AdipoR - adiponectin receptor; FGF21 - fibroblast growth factor 21; Angptl8 - angiopoietin-related protein 8; PirB - murine paired immunoglobulin receptor B; NF-κB - nuclear factor kappa-light-chain-enhancer of activated B cells; Akt - protein kinase B; IGF-1 - insulin-like growth factor 1; GSK-3β - glycogen synthase kinase 3 beta; RBP4 - retinol binding protein 4; IL-6 - interleukin 6; IL-8 - interleukin 8; CCL2 - chemokine (C-C motif) ligand 2; PTEN - phosphatase and tensin homolog; mTORC1 - mTOR complex 1; SSTR - somatostatin receptor; GLP-1 - glucagon-like peptide-1; GLP1R - GLP1 receptor; GHSR - growth hormone secretagogue receptor; SCFA - shot chain fatty acid; HDAC3 - histone deacetylase 3; STAT3 - signal transduction and activator of transcription 3; ILC3 - type 3 innate lymphoid cells; NFIL3 - nuclear factor interleukin 3 regulated.