Molecular pharmacology of histamine system

组胺是一种最古老的生物胺，在平滑肌收缩、增加血管渗透性、胃酸分泌等多种功能中起重要作用。近年来，分子生物学在组胺领域有了很大的进展，我们在开始这个项目的时候，对这四个挑战进行了开放的研究。(1)组胺转运体；(2)H3受体的克隆；(3)组胺形成酶、l -组氨酸脱羧酶（HDC）基因表达的调控及HDC基因敲除小鼠的产生；(4)组胺代谢酶、组胺n -甲基转移酶基因的定位。(1)我们可以证明从大鼠大脑皮层分离的突触体和从hdc基因敲除小鼠制备的骨髓来源肥大细胞中存在组胺转运体。(2)不幸的是，美国的Lovenberg报道了H3受体的克隆。(3)我们发现转录起始位点附近的CpG岛的去甲基化在HDC的表达中很重要。采用常规同源重组法制备HDC基因敲除小鼠。KO小鼠在过敏反应、胃酸分泌、昼夜节律等方面出现紊乱，可作为组胺相关病理研究的模型。此外，在这些小鼠中发现的许多其他系统的网络存在中，组胺在生理学上的新功能很可能是无法检测到的。(4)支气管哮喘患者HMT基因结构多样，提示HMT基因可能是哮喘相关基因。

Histamine is an oldest biogenic amine and plays important roles in many functions such as smooth muscle contraction, incease in valucular permeability gastric acid secretion and so on. Recently there have many great advances in the molecular biology in the field of histamine, and the four challenges were open to research when we began this project. (1) histamine transporter, (2) cloning of H3 receptors, (3) regulation of gene expression of histamine forming enzyme, L-histidine decarboxylase (HDC) and production of HDC gene knock-out mice, and (4) clining of the gene for histamine metabolizing enzyme, histamine N-methyltranferase.(1) We could demonstrate the presence of histamine transporter in synaptosomes isolated from rat cerebral cortex and bone marrow derived mast cells prepared from HDC-gene knock-out mice.(2) Unfortunately, the cloning of H3 receptors was reported by Lovenberg from USA.(3) We showed that the demethylation of CpG islands in the vicinity of transcription initiation site is important in the expression of HDC. We produced HDC gene knockout mice by routine homologous recombination method. The KO mice showed disturbances in allergic reactions, gastric acid secretion, circadian rhythm and so on, and thus, these mice may be useful for a model for studies on histamine related pathological conditions. Moreover, there is a high possibility that a new function of histamine in physiology that has been undetectable in the presence of netword of many other systems discovered in these mice.(4) The structure of the HMT gene is multiple in patients of broncial asthma, suggesting the possibility that HMT gene is a asthma-related one.