Studies on histamine with L-histidine decarboxylase, a histamine-forming enzyme, as a probe: from purification to gene knockout

Abstract

I have been studying the functions of the histaminergic neuron system in the brain, the location and distribution of which we elucidated with antibody raised against L-histidine decarboxylase (a histamine-forming enzyme) as a marker in 1984. For this purpose, we used two methods employing (1) pharmacological agents like alpha-fluoromethylhistidine, an HDC inhibitor, and agonists and antagonists of H1, H2 and H3 receptors and (2) knockout mice of the HDC- and H1- and H2-receptor genes. In some cases, we used positron emission tomography (PET) of H1 receptors in living human brains. It turned out that histamine neurons are involved in many brain functions, and particularly, histamine is one of the neuron systems to keep awakefulness. Histamine also plays important roles in bioprotection against various noxious or unfavorable stimuli (convulsion, nociception, drug sensitization, ischemic lesions, stress and so on). Finally, I briefly described interesting phenotypes found in peripheral tissues of HDC-KO mice; the most striking finding is that mast cells in HDC-KO mice are fewer in number, smaller in size and less dense in granule density than those of wild type mice, indicating that histamine is related to the proliferation and differentiation of mast cells. In conclusion, histamine is important not only in the central and peripheral systems as studied so far but also may be related to some new functions that are now under investigation in our laboratories.