Abstract
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.
Highlights
A biogenic amine formed by decarboxylation of the amino acid L-histidine [1], is found in large quantities in most tissues, mainly in the granules of mast cells, numerous other cell types are capable of histamine synthesis as well [2]
Control experiments consistently showed that F9 embryo carcinoma (EC) and D3 ES cells spontaneously reacted toward ATP (50 M) and bradykinin (1 M) but never did show uninduced histamine responses (n ϭ 29)
These results suggest that the failure of F9 EC cells to react to histamine under uninduced conditions is due to the absence of high affinity histamine binding activity, and that induction of histamine responsiveness is caused by a rapid increase of high affinity histamine binding sites on the plasma membrane
Summary
A biogenic amine formed by decarboxylation of the amino acid L-histidine [1], is found in large quantities in most tissues, mainly in the granules of mast cells, numerous other cell types are capable of histamine synthesis as well [2]. 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.
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