Bloemers S M, Verheule S, Peppelenbosch M P, Smit M J, Tertoolen L G, de Laat S
Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Utrecht, The Netherlands.
J Biol Chem. 1998 Jan 23;273(4):2249-55. doi: 10.1074/jbc.273.4.2249.
Histamine regulates a variety of physiological processes including inflammation, gastric acid secretion, and neurotransmission. The cellular response to histamine is subject to dynamic control, and exaggerated histamine reactivity in response to cysteinyl leukotrienes and other stimuli is important in a variety of different pathological conditions. The molecular mechanisms controlling histamine responsiveness are still unresolved. In investigating histamine responses in embryonic stem (ES5) and F9 embryonic carcinoma cells, we encountered a novel mechanism controlling the cellular reaction to histamine. Unstimulated cells displayed neither [3H]pyrilamine binding nor histamine-induced increases in cytosolic Ca2+ levels. Pretreatment of these cells, however, with leukotriene D4, leukotriene E4, serotonin, or fetal calf serum induced an immediate and transient ability of these cells to respond to histamine with an increase in cytosolic Ca2+ levels. This effect could be inhibited by pertussis toxin and was mimicked by GTP analogues. Importantly, the latter compounds also provoked immediate high affinity [3H]pyrilamine binding. We conclude that in these cells histamine responsiveness is directly controlled by pertussis toxin-sensitive G protein-coupled receptors, whose activation enables the H1 receptor to bind its ligand. These findings define a novel mechanism for regulating histamine H1 receptor activity and provide for the first time molecular insight into the mechanism by which cysteinyl leukotrienes and other external stimuli can increase histamine responsiveness.
组胺调节多种生理过程，包括炎症、胃酸分泌和神经传递。细胞对组胺的反应受到动态控制，并且在对半胱氨酰白三烯和其他刺激的反应中，组胺反应性的过度增强在多种不同病理状况中具有重要意义。控制组胺反应性的分子机制仍未得到解决。在研究胚胎干细胞（ES5）和F9胚胎癌细胞中的组胺反应时，我们发现了一种控制细胞对组胺反应的新机制。未受刺激的细胞既不显示[3H]吡拉明结合，也不显示组胺诱导的胞质Ca2+水平升高。然而，用白三烯D4、白三烯E4、5-羟色胺或胎牛血清预处理这些细胞，会诱导这些细胞立即且短暂地具备以胞质Ca2+水平升高来响应组胺的能力。这种效应可被百日咳毒素抑制，并被GTP类似物模拟。重要的是，后一类化合物还会引发立即的高亲和力[3H]吡拉明结合。我们得出结论，在这些细胞中，组胺反应性直接由百日咳毒素敏感的G蛋白偶联受体控制，其激活使H1受体能够结合其配体。这些发现定义了一种调节组胺H1受体活性的新机制，并首次在分子层面深入了解了半胱氨酰白三烯和其他外部刺激可增加组胺反应性的机制。
