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 Ca(2+) concentration ([Ca(2+)](i)) through the activation of Ca(V)1.3 L-type Ca(2+) channels and Ca(2+)-induced Ca(2+) release from ryanodine receptor-mediated internal stores. RESULTS: In the current study, we explored the underlying mechanisms with various techniques including Ca(2+)- 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(V)1.3 Ca(2+) channels in SCN neurons. We found that histamine elicited Cl(−) efflux and increased [Ca(2+)](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(V)1.3 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.