AUTHOR=Morioka Eri , Kanda Yuzuki , Koizumi Hayato , Miyamoto Tsubasa , Ikeda Masayuki 

TITLE=Histamine Regulates Molecular Clock Oscillations in Human Retinal Pigment Epithelial Cells via H1 Receptors

JOURNAL=Frontiers in Endocrinology

VOLUME=9

YEAR=2018

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2018.00108

DOI=10.3389/fendo.2018.00108

ISSN=1664-2392

ABSTRACT=<p>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 (<italic>Bmal1-luciferase</italic>) and intracellular Ca<sup>2+</sup> concentrations (<italic>YC3.6</italic>). We observed concentration-dependent increases in cytosolic Ca<sup>2+</sup> concentrations after treatment with histamine (1–100 µM) and complete suppression of histamine-induced Ca<sup>2+</sup> mobilizations by H<sub>1</sub> histamine receptor (H<sub>1</sub>R) antagonist <italic>d</italic>-chlorpheniramine (<italic>d</italic>-CPA) in hRPE-YC cells. Consistently, real-time RT-PCR assays revealed that H<sub>1</sub>R showed the highest expression among the four subtypes (H<sub>1</sub>–H<sub>4</sub>) of histamine receptors in hRPE-YC cells. Stimulation of hRPE-YC cells with histamine transiently increased nuclear localization of phosphorylated Ca<sup>2+</sup>/cAMP-response element-binding protein that regulates clock gene transcriptions. Administration of histamine also shifted the <italic>Bmal1-luciferase</italic> rhythms with a type-1 phase-response curve, similar to previous results with carbachol stimulations. Treatment of hRPE-YC cells with <italic>d</italic>-CPA or with more specific H<sub>1</sub>R antagonist, ketotifen, blocked the histamine-induced phase shifts. Furthermore, an H<sub>2</sub> histamine receptor agonist, amthamine, had little effect on the <italic>Bmal1-luciferase</italic> rhythms. Although the function of the <italic>in vivo</italic> histaminergic system within the eye remains obscure, the present results suggest histaminergic control of the molecular clock <italic>via</italic> H<sub>1</sub>R in retinal pigment epithelial cells. Also, since <italic>d</italic>-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.</p>