Molecular pharmacology of histamine system

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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.