Histamine 1 receptor-G_βγ-cAMP/PKA-CFTR pathway mediates the histamine-induced resetting of the suprachiasmatic circadian clock

Background: Recent evidence indicates that histamine, acting on histamine 1 receptor (H1R), resets the circadian clock in the mouse suprachiasmatic nucleus (SCN) by increasing intracellular Ca²⁺ concentration ([Ca²⁺]_i) through the activation of Ca_V1.3 L-type Ca²⁺ channels and Ca²⁺-induced Ca²⁺ release from ryanodine receptor-mediated internal stores. Results: In the current study, we explored the underlying mechanisms with various techniques including Ca²⁺- and Cl^--imaging and extracellular single-unit recording. Our hypothesis was that histamine causes Cl^- efflux through cystic fibrosis transmembrane conductance regulator (CFTR) to elicit membrane depolarization needed for the activation of Ca_V1.3 Ca²⁺ channels in SCN neurons. We found that histamine elicited Cl^- efflux and increased [Ca²⁺]_i in dissociated mouse SCN cells. Both of these events were suppressed by bumetanide [Na⁺-K⁺-2Cl^- cotransporter isotype 1 (NKCC1) blocker], CFTR_inh-172 (CFTR inhibitor), gallein (G_βγ protein inhibitor) and H89 [protein kinase A (PKA) inhibitor]. By itself, H1R activation with 2-pyridylethylamine increased the level of cAMP in the SCN and this regulation was prevented by gallein. Finally, histamine-evoked phase shifts of the circadian neural activity rhythm in the mouse SCN slice were blocked by bumetanide, CFTR_inh-172, gallein or H89 and were not observed in NKCC1 or CFTR KO mice. Conclusions: Taken together, these results indicate that histamine recruits the H1R-G_βγ-cAMP/PKA pathway in the SCN neurons to activate Ca_V1.3 channels through CFTR-mediated Cl^- efflux and ultimately to phase-shift the circadian clock. This pathway and NKCC1 may well be potential targets for agents designed to treat problems resulting from the disturbance of the circadian system.