Fig. 6

Proposed signaling pathway for histamine-induced resetting of the circadian pacemaker in the SCN. ① A subset of SCN neurons are loaded with Cl⁻ by the action of the Cl⁻ importer NKCC1. ② H1R stimulation by histamine at early night results in the production of activated G_βγ protein in these cells. ③ The activated G_βγ protein stimulates adenylate cyclase (AC) to produce cAMP from ATP. ④ PKA activated by cAMP opens the Cl⁻ channel CFTR. ⑤ The efflux of Cl⁻ through CFTR down the electrochemical gradient results in membrane depolarization. ⑥ In response to this membrane depolarization, the Ca_V1.3 L-type voltage-gated Ca²⁺ channel (VGCC) is activated. ⑦ The resulting Ca²⁺ influx through Ca_V1.3 VGCC induces Ca²⁺ release from the endoplasmic reticulum (ER) through RyR. ⑧ The consequent increase in [Ca²⁺]_i leads to phase delay of the circadian clock