Abstract
Vertebrate eyes are known to contain circadian clocks, but their regulatory mechanisms remain largely unknown. To address this, we used a cell line from human retinal pigment epithelium (hRPE-YC) with stable coexpression of reporters for molecular clock oscillations (Bmal1-luciferase) and intracellular Ca2+ concentrations (YC3.6). We observed concentration-dependent increases in cytosolic Ca2+ concentrations after treatment with histamine (1–100 µM) and complete suppression of histamine-induced Ca2+ mobilizations by H1 histamine receptor (H1R) antagonist d-chlorpheniramine (d-CPA) in hRPE-YC cells. Consistently, real-time RT-PCR assays revealed that H1R showed the highest expression among the four subtypes (H1–H4) of histamine receptors in hRPE-YC cells. Stimulation of hRPE-YC cells with histamine transiently increased nuclear localization of phosphorylated Ca2+/cAMP-response element-binding protein that regulates clock gene transcriptions. Administration of histamine also shifted the Bmal1-luciferase rhythms with a type-1 phase-response curve, similar to previous results with carbachol stimulations. Treatment of hRPE-YC cells with d-CPA or with more specific H1R antagonist, ketotifen, blocked the histamine-induced phase shifts. Furthermore, an H2 histamine receptor agonist, amthamine, had little effect on the Bmal1-luciferase rhythms. Although the function of the in vivo histaminergic system within the eye remains obscure, the present results suggest histaminergic control of the molecular clock via H1R in retinal pigment epithelial cells. Also, since d-CPA and ketotifen have been widely used (e.g., to treat allergy and inflammation) in our daily life and thus raise a possible cause for circadian rhythm disorders by improper use of antihistamines.
Highlights
The histaminergic system in the central nervous system controls diverse physiological functions including sleeping–waking, thermoregulation, and feeding [1]
Histaminergic projections from the brain to the retina have been shown to exist in rodents and primates [3,4,5,6], but knowledge on Abbreviations: ANOVA, analysis of variance; CPA, chlorpheniramine; cAMP response element-binding protein (CREB), Ca2+/cAMP-response element-binding protein; CT, circadian time; H1R, H1 histamine receptor; H2R, H2 histamine receptor; HDC, histidine decarboxylase; DAPI, 4′,6-diamidino-2-phenylindole; pCREB, phosphorylated CREB; PRC, phase-response curve; RPE, retinal pigment epithelial; SCN, suprachiasmatic nucleus; TMN, tuberomammillary nucleus
The results revealed that H1R showed the highest expression among the four histamine receptor subtypes with no difference in the levels between subjective daytime and subjective night-time
Summary
The histaminergic system in the central nervous system controls diverse physiological functions including sleeping–waking, thermoregulation, and feeding [1]. To achieve these functions, histaminergic neurons in the tuberomammillary nucleus (TMN) of the posterior hypothalamus send long-distance axons into diverse brain areas [2]. Histamine significantly reduced hyperpolarization-activated currents recorded from cones in monkeys [8] and modulated retinal ganglion cell firings in rats and monkeys [9]. No apparent changes in retinal structures and functions were identified in HDC knockout (HDC−/−) mice [11], and retinal histaminergic regulations remain controversial
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