Abstract
BackgroundRecent 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.ResultsIn 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.ConclusionsTaken 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.
Highlights
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 ([intracellular calcium concentration (Ca2+]i)) through the activation of CaV1.3 L-type Ca2+ channels and Ca2+-induced Ca2+ release from ryanodine receptor-mediated internal stores
We demonstrated that histamine, acting on H1R, increases intracellular Ca2+ concentration ([Ca2+]i) in mouse SCN neurons by a novel mechanism driven by CaV1.3 L-type Ca2+ channels as well as Ca2+-induced Ca2+ release from ryanodine receptor (RyR)-mediated internal stores and this is the molecular mechanism underlying the histamine-induced phase delay of circadian neural activity rhythm in the SCN [12]
In order to better understand the histaminergic regulation of Cl− in SCN neurons, we explored the possible role of cystic fibrosis transmembrane conductance regulator (CFTR), the protein kinase A (PKA)-activated Cl− channel
Summary
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. We demonstrated that histamine, acting on H1R, increases intracellular Ca2+ concentration ([Ca2+]i) in mouse SCN neurons by a novel mechanism driven by CaV1.3 L-type Ca2+ channels as well as Ca2+-induced Ca2+ release from ryanodine receptor (RyR)-mediated internal stores and this is the molecular mechanism underlying the histamine-induced phase delay of circadian neural activity rhythm in the SCN [12]. We present results indicating that the Gβγ-cAMP/PKA-CFTR pathway links H1R to L-type Ca2+ channels and this pathway is essential for the phase delay of the circadian clock induced by histamine
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