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


Yoon Sik Kim, Young-Beom Kim, Woong Bin Kim, Seung Won Lee, Seog Bae Oh, Hee-Chul Han, C. Justin LeeEmail author, Christopher S. Colwell and Yang In Kim

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 CaV1.3 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 CaV1.3 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], CFTRinh-172 (CFTR inhibitor), gallein (Gβγ 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, CFTRinh-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-Gβγ-cAMP/PKA pathway in the SCN neurons to activate CaV1.3 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.

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Published
March, 2016

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