4 Neither the release component of the ATP response (50 jiM) nor the caffeine (3 mM)-induced Ca2+ release were found to be affected by desensitization with 100 tIM histamine. However, the second phase of the ATP response was significantly reduced after desensitization with histamine (control cells: 516 ± 33 nM; desensitized cells: 331 + 96 nM, n = 4, P < 0.05). 5 Activation of protein kinase C (PKC) by phorbol-12-myristate-1 3-acetate was found to inhibit the histamine as well as ATP-induced Ca2" response in a dose-dependent manner.6 In PKC downregulated cells the second phase of the histamine-induced Ca2+ response was significantly elevated, indicating the involvement of PKC in the negative feedback on the Ca2+ influx (control cells: second phase: 601 ± 52 nM (n = 11); PKC downregulated cells: second phase: 890 ± 90nM, n = I0, P<0.05).7 Homologous desensitization of H, receptor responsiveness was still observed in PKC downregulated cells, implying the rapid activation of a regulatory mechanism other than PKC.8 Based on our experimental data we suggest that short-term desensitization of the histamine H, receptor evolves from two different processes: a selective reduction of the histamine-induced Ca2+ release, mediated by a PKC-independent pathway, and a non-selective inhibition of the receptormediated Ca2+ influx activated by a PKC-dependent pathway.
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 [ 3 H]pyrilamine binding nor histamineinduced increases in cytosolic Ca 2؉ levels. Pretreatment of these cells, however, with leukotriene D 4 , leukotriene E 4 , serotonin, or fetal calf serum induced an immediate and transient ability of these cells to respond to histamine with an increase in cytosolic Ca 2؉ levels. This effect could be inhibited by pertussis toxin and was mimicked by GTP analogues. Importantly, the latter compounds also provoked immediate high affinity [ 3 H]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 H 1 receptor to bind its ligand. These findings define a novel mechanism for regulating histamine H 1 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.
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