Kim, Yoon Sik Kim, Young-Beom Kim, Woong Bin Lee, Seung Won Oh, Seog Bae Han, Hee-Chul Lee, C. Justin Colwell, Christopher S. Kim, Yang In 2024-01-20T04:04:16Z 2024-01-20T04:04:16Z 2021-09-05 2016-05-06 1756-6606 https://pubs.kist.re.kr/handle/201004/124073 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 Ca(V)1.3 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 Ca(V)1.3 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 (G(beta gamma) 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-G(beta gamma)-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. English BIOMED CENTRAL LTD BETA-GAMMA-SUBUNITS CYSTIC-FIBROSIS NERVOUS-SYSTEM PHASE-SHIFTS HISTIDINE-DECARBOXYLASE CHLORIDE CONDUCTANCE NEURONS NUCLEUS RECEPTOR ACTIVATION Histamine 1 receptor-G(beta gamma)-cAMP/PKA-CFTR pathway mediates the histamine-induced resetting of the suprachiasmatic circadian clock Article 10.1186/s13041-016-0227-1 1 MOLECULAR BRAIN, v.9 MOLECULAR BRAIN 9 scie scopus 000376866000002 2-s2.0-84969524196 Neurosciences Neurosciences & Neurology Article BETA-GAMMA-SUBUNITS CYSTIC-FIBROSIS NERVOUS-SYSTEM PHASE-SHIFTS HISTIDINE-DECARBOXYLASE CHLORIDE CONDUCTANCE NEURONS NUCLEUS RECEPTOR ACTIVATION Calcium CFTR Chloride Circadian rhythm Histamine NKCC1 Suprachiasmatic nucleus