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 Lee, Christopher S. Colwell, Yang In Kim

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)


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.

Original languageEnglish
Article number227
JournalMolecular brain
Issue number1
Publication statusPublished - 2016 May 6

Bibliographical note

Funding Information:
This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korea government (MSIP) to Y. I Kim (NRF-2011-0022529 and No. 2014R1A2A1A11049900) and Korea University Grant (K1031781; Y.I.K), and by KIST institutional program, Project No. 2E25210 (C.J.L.), and Brain Research Program through the National Research Foundation of Korea funded by the Ministry of Science, ICT & Future Planning, NRF-2012M3C7A1055412 (C.J.L.), and WCI Program of National Research Foundation (C.J.L.). Y.S.K., Y.-B.K., W.B.K., S.W.L. and Y.I.K. were supported by the Brain Korea 21 Project from 2009 to 2014. Y.S.K. and C.S.C received support from the O’Keefe Foundation.

Publisher Copyright:
© 2016 Kim et al.


  • CFTR
  • Calcium
  • Chloride
  • Circadian rhythm
  • Histamine
  • NKCC1
  • Suprachiasmatic nucleus

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience


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