title: Histamine 1 receptor-Gβγ-cAMP/PKA-CFTR pathway mediates the histamine-induced resetting of the suprachiasmatic circadian clock.
abstract: 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 CaV1.3 L-type Ca(2+) channels and Ca(2+)-induced Ca(2+) release from ryanodine receptor-mediated internal stores.
  
  
  
  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 CaV1.3 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], 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.
  
  
  
  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.
authors.affiliation: Department of Physiology and Neuroscience Research Institute, Korea University College of Medicine, 126-1 Anam-dong 5-ga, Seoul, 136-705, Republic of Korea.|Department of Psychiatry & Biobehavioral Sciences, University of California-Los Angeles, 760 Westwood Plaza, Los Angeles, CA, 90024, USA.
authors.forename: Yoon Sik
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Department of Physiology and Neuroscience Research Institute, Korea University College of Medicine, 126-1 Anam-dong 5-ga, Seoul, 136-705, Republic of Korea.
authors.forename: Young-Beom
authors.initials: YB
authors.lastname: Kim
authors.affiliation: Department of Physiology and Neuroscience Research Institute, Korea University College of Medicine, 126-1 Anam-dong 5-ga, Seoul, 136-705, Republic of Korea.
authors.forename: Woong Bin
authors.initials: WB
authors.lastname: Kim
authors.affiliation: Department of Physiology and Neuroscience Research Institute, Korea University College of Medicine, 126-1 Anam-dong 5-ga, Seoul, 136-705, Republic of Korea.
authors.forename: Seung Won
authors.initials: SW
authors.lastname: Lee
authors.affiliation: Pain Cognitive Function Research Center, Dental Research Institute and Department of Neurobiology and Physiology, Seoul National University, Seoul, 110-749, Republic of Korea.
authors.forename: Seog Bae
authors.initials: SB
authors.lastname: Oh
authors.affiliation: Department of Physiology and Neuroscience Research Institute, Korea University College of Medicine, 126-1 Anam-dong 5-ga, Seoul, 136-705, Republic of Korea.
authors.forename: Hee-Chul
authors.initials: HC
authors.lastname: Han
authors.affiliation: Center for Neuroscience and Functional Connectomics, Korea Institute of Science and Technology, Seoul, 136-791, Republic of Korea. cjl@kist.re.kr.
authors.forename: C Justin
authors.initials: CJ
authors.lastname: Lee
authors.affiliation: Department of Psychiatry & Biobehavioral Sciences, University of California-Los Angeles, 760 Westwood Plaza, Los Angeles, CA, 90024, USA.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Colwell
authors.affiliation: Department of Physiology and Neuroscience Research Institute, Korea University College of Medicine, 126-1 Anam-dong 5-ga, Seoul, 136-705, Republic of Korea. yikim@korea.ac.kr.
authors.forename: Yang In
authors.initials: YI
authors.lastname: Kim
mesh_terms: D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism; D057906:Circadian Clocks / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D044387:GTP-Binding Protein beta Subunits / Q000378:metabolism*; D044388:GTP-Binding Protein gamma Subunits / Q000378:metabolism*; D006632:Histamine / Q000494:pharmacology*; D015640:Ion Channel Gating / Q000187:drug effects; D008297:Male; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011969:Receptors, Histamine H1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D064506:Solute Carrier Family 12, Member 2 / Q000378:metabolism; D013493:Suprachiasmatic Nucleus / Q000378:metabolism*
chemical_list: D020746:Calcium Channels, L-Type; D002712:Chlorides; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D011969:Receptors, Histamine H1; C578878:Slc12a2 protein, mouse; D064506:Solute Carrier Family 12, Member 2; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D006632:Histamine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: CFTR; Calcium; Chloride; Circadian rhythm; Histamine; NKCC1; Suprachiasmatic nucleus