Three major feedback loops regulate the mammalian circadian clock.

The core negative feedback loop is between PER:CRY and BMAL1:CLOCK. The two sources of additional feedback are negative feedback between REV-ERB and BMAL1 and positive feedback between ROR and BMAL1. PER1/2, CRY1/2, REV-ERBα/β and RORα/β are simplified to PER, CRY, REV-ERB and ROR, respectively. Solid lines indicate chemical reactions; the T-shaped reactions indicate reversible binding of proteins to form multicomponent complexes. Dashed lines indicate regulatory signals (positive regulation = barbed arrow, and negative regulation = blunt arrow).