Yoshikawa Takeo, Nakamura Tadaho, Yanai Kazuhiko
Department of Pharmacology, Tohoku University Graduate School of Medicine.
Division of Pharmacology, Tohoku Medical and Pharmaceutical University.
Nihon Yakurigaku Zasshi. 2018;152(1):16-20. doi: 10.1254/fpj.152.16.
Histamine acts as a neurotransmitter to regulate various physiological functions in CNS. Recent reports showed the involvement of histaminergic dysfunction in neurological disorders. Neurotransmitter clearance is essential to determine brain neurotransmitter concentration. However, molecular mechanism of brain histamine clearance remains largely unknown. First, we examined the molecular mechanism of histamine clearance in primary human astrocytes. We demonstrated that extracellular histamine was transported through organic cation transporter (OCT) 3 and plasma membrane monoamine transporter (PMAT), and subsequently intracellular histamine was inactivated by histamine N-methyltransferase (HNMT) in cytosol. Next, we generated HNMT knockout (HNMT KO) mice to investigate the role of HNMT in vivo. HNMT deficiency dramatically enhanced brain histamine concentration, indicating the important role of HNMT in histamine inactivation. HNMT KO mice showed high aggression via abnormal histamine H2 receptor (H2R) activation and the disrupted sleep-wake cycle via excessive H1R activation. These observations show that HNMT plays a pivotal role in regulating brain histamine concentration, and modulates aggression as well as the sleep-wake cycle. Although importance of OCT3 and PMAT in histaminergic nervous system remains still unknown, our preliminary data show the contribution of PMAT to brain histamine concentration. We also try to find novel inhibitors targeting brain histamine clearance. We hope our study could lead a better understanding of neuropsychiatric disorders and the development of new drugs inhibiting HNMT, OCT3 and PMAT activity.
组胺作为一种神经递质，在中枢神经系统中调节各种生理功能。最近的报告显示组胺能功能障碍与神经疾病有关。神经递质清除对于确定脑内神经递质浓度至关重要。然而，脑内组胺清除的分子机制仍 largely 未知。首先，我们研究了原代人星形胶质细胞中组胺清除的分子机制。我们证明细胞外组胺通过有机阳离子转运体（OCT）3 和质膜单胺转运体（PMAT）进行转运，随后细胞内组胺在胞质溶胶中被组胺 N-甲基转移酶（HNMT）灭活。接下来，我们生成了 HNMT 基因敲除（HNMT KO）小鼠，以研究 HNMT 在体内的作用。HNMT 缺乏显著提高了脑内组胺浓度，表明 HNMT 在组胺灭活中起重要作用。HNMT KO 小鼠通过异常激活组胺 H2 受体（H2R）表现出高攻击性，并通过过度激活 H1R 破坏睡眠-觉醒周期。这些观察结果表明，HNMT 在调节脑内组胺浓度方面起关键作用，并调节攻击性以及睡眠-觉醒周期。虽然 OCT3 和 PMAT 在组胺能神经系统中的重要性仍然未知，但我们的初步数据显示 PMAT 对脑内组胺浓度有贡献。我们还试图寻找针对脑内组胺清除的新型抑制剂。我们希望我们的研究能够更好地理解神经精神疾病，并推动抑制 HNMT、OCT3 和 PMAT 活性的新药开发。
