PMID- 27153809 OWN - NLM STAT- MEDLINE DCOM- 20171106 LR - 20181113 IS - 1756-6606 (Electronic) IS - 1756-6606 (Linking) VI - 9 IP - 1 DP - 2016 May 6 TI - Histamine 1 receptor-Gbetagamma-cAMP/PKA-CFTR pathway mediates the histamine-induced resetting of the suprachiasmatic circadian clock. PG - 49 LID - 10.1186/s13041-016-0227-1 [doi] LID - 49 AB - 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 CaV1.3 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 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 (Gbetagamma 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-Gbetagamma-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. FAU - Kim, Yoon Sik AU - Kim YS AD - Department of Physiology and Neuroscience Research Institute, Korea University College of Medicine, 126-1 Anam-dong 5-ga, Seoul, 136-705, Republic of Korea. AD - Department of Psychiatry & Biobehavioral Sciences, University of California-Los Angeles, 760 Westwood Plaza, Los Angeles, CA, 90024, USA. FAU - Kim, Young-Beom AU - Kim YB AD - Department of Physiology and Neuroscience Research Institute, Korea University College of Medicine, 126-1 Anam-dong 5-ga, Seoul, 136-705, Republic of Korea. FAU - Kim, Woong Bin AU - Kim WB AD - Department of Physiology and Neuroscience Research Institute, Korea University College of Medicine, 126-1 Anam-dong 5-ga, Seoul, 136-705, Republic of Korea. FAU - Lee, Seung Won AU - Lee SW AD - Department of Physiology and Neuroscience Research Institute, Korea University College of Medicine, 126-1 Anam-dong 5-ga, Seoul, 136-705, Republic of Korea. FAU - Oh, Seog Bae AU - Oh SB AD - Pain Cognitive Function Research Center, Dental Research Institute and Department of Neurobiology and Physiology, Seoul National University, Seoul, 110-749, Republic of Korea. FAU - Han, Hee-Chul AU - Han HC AD - Department of Physiology and Neuroscience Research Institute, Korea University College of Medicine, 126-1 Anam-dong 5-ga, Seoul, 136-705, Republic of Korea. FAU - Lee, C Justin AU - Lee CJ AD - Center for Neuroscience and Functional Connectomics, Korea Institute of Science and Technology, Seoul, 136-791, Republic of Korea. cjl@kist.re.kr. FAU - Colwell, Christopher S AU - Colwell CS AD - Department of Psychiatry & Biobehavioral Sciences, University of California-Los Angeles, 760 Westwood Plaza, Los Angeles, CA, 90024, USA. FAU - Kim, Yang In AU - Kim YI AD - 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. LA - eng PT - Journal Article DEP - 20160506 PL - England TA - Mol Brain JT - Molecular brain JID - 101468876 RN - 0 (Calcium Channels, L-Type) RN - 0 (Chlorides) RN - 0 (GTP-Binding Protein beta Subunits) RN - 0 (GTP-Binding Protein gamma Subunits) RN - 0 (Receptors, Histamine H1) RN - 0 (Slc12a2 protein, mouse) RN - 0 (Solute Carrier Family 12, Member 2) RN - 126880-72-6 (Cystic Fibrosis Transmembrane Conductance Regulator) RN - 820484N8I3 (Histamine) RN - E0399OZS9N (Cyclic AMP) RN - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases) SB - IM MH - Animals MH - Calcium Channels, L-Type/metabolism MH - Chlorides/metabolism MH - *Circadian Clocks/drug effects MH - Cyclic AMP/*metabolism MH - Cyclic AMP-Dependent Protein Kinases/metabolism MH - Cystic Fibrosis Transmembrane Conductance Regulator/*metabolism MH - GTP-Binding Protein beta Subunits/*metabolism MH - GTP-Binding Protein gamma Subunits/*metabolism MH - Histamine/*pharmacology MH - Ion Channel Gating/drug effects MH - Male MH - Mice, Inbred C57BL MH - Models, Biological MH - Neurons/drug effects/metabolism MH - Receptors, Histamine H1/*metabolism MH - Signal Transduction/drug effects MH - Solute Carrier Family 12, Member 2/metabolism MH - Suprachiasmatic Nucleus/*metabolism PMC - PMC4858891 OTO - NOTNLM OT - CFTR OT - Calcium OT - Chloride OT - Circadian rhythm OT - Histamine OT - NKCC1 OT - Suprachiasmatic nucleus EDAT- 2016/05/08 06:00 MHDA- 2017/11/07 06:00 PMCR- 2016/05/06 CRDT- 2016/05/08 06:00 PHST- 2016/03/22 00:00 [received] PHST- 2016/04/15 00:00 [accepted] PHST- 2016/05/08 06:00 [entrez] PHST- 2016/05/08 06:00 [pubmed] PHST- 2017/11/07 06:00 [medline] PHST- 2016/05/06 00:00 [pmc-release] AID - 10.1186/s13041-016-0227-1 [pii] AID - 227 [pii] AID - 10.1186/s13041-016-0227-1 [doi] PST - epublish SO - Mol Brain. 2016 May 6;9(1):49. doi: 10.1186/s13041-016-0227-1.