SENSITIZATION OF THE HISTAMINE H-1 RECEPTOR BY INCREASED LIGAND AFFINITY

Histamine regulates a variety of physiological processes including inf lammation, 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 s timuli is important in a variety of different pathological conditions, The molecular mechanisms controlling histamine responsiveness are sti ll unresolved, In investigating histamine responses in embryonic stem (ES5) and F9 embryonic carcinoma cells, we encountered a novel mechani sm controlling the cellular reaction to histamine, Unstimulated cells displayed neither [H-3]pyrilamine binding nor histamine-induced increa ses in cytosolic Ca2+ levels, Pretreatment of these cells, however, wi th leukotriene D-4, leukotriene E-4, serotonin, or fetal calf serum in duced 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, Im portantly, the latter compounds also provoked immediate high affinity [H-3]pyrilamine binding, We conclude that in these cells histamine res ponsiveness is directly controlled by pertussis toxin-sensitive G prot ein-coupled receptors, whose activation enables the H-1 receptor to bi nd its ligand, These findings define a novel mechanism for regulating histamine H-1 receptor activity and provide for the first time molecul ar insight into the mechanism by which cysteinyl leukotrienes and othe r external stimuli can increase histamine responsiveness.