Desensitization of histamine H1 receptor-mediated inositol phosphate production in HeLa cells

Content Provider	Scilit
Author	Bristow, David R. Zamani, M. Reza
Copyright Year	1993
Description	Journal: British Journal of Pharmacology
Abstract	1 Histamine stimulated the accumulation of total $[^{3}$H]-inositol phosphates $(IP_{n}$) in control HeLa cells with an $EC_{50}$ of 3.7 ± 0.7 μm in the presence of 10 mm LiCl. The maximum response to histamine after 15 min incubation was 43 ± 5% over basal accumulation and occurred at a concentration of 1 mm histamine. 2 The histamine-induced $IP_{n}$ production in HeLa cells was confirmed as $H_{1}$ receptor-mediated, since the $H_{1}$ antagonist mepyramine $(10^{−6}$ m) inhibited the histamine response $(10^{−4}$ m) by 83 ± 7%, whereas the $H_{2}$ antagonist, ranitidine $(10^{−4}$ m), and $H_{3}$ antagonist, thioperamide $(10^{−6}$ m), were ineffective. 3 Histamine $(10^{−4}$ m) pretreatment of HeLa cells for 30 min desensitized the subsequent histamine-induced $IP_{n}$ accumulation. The desensitized cells accumulated $IP_{n}$ in response to histamine with an $EC_{50}$ of 1.7 ± 0.7 μm after 15 min incubation. The maximum histamine-induced $IP_{n}$ accumulation at $10^{−4}$ m was 19 ± 5% over basal and was significantly lower (P < 0.03) than the maximum response in control cells. 4 The desensitization of histamine-induced $IP_{n}$ accumulation was time-dependent and, at a desensitizing histamine concentration of $10^{−4}$ m, the half-maximal attenuation occurred after approximately 9 min and maximum desensitization was achieved by 15–20 min. The desensitization of the $IP_{n}$ accumulation was a reversible phenomenon and full recovery of the response occurred 150 min after the removal of the desensitizing histamine-containing medium. The half-time for the recovery of the histamine-induced response was estimated at 120 min. 5 Bradykinin stimulated $IP_{n}$ accumulation in HeLa cells, and the $EC_{50}$ in control cells of 1.9 ± 0.2 nm was not significantly different from the $EC_{50}$ value from histamine-pretreated cells of 1.6 ± 0.9 nm. The bradykinin response at 1 μm was 194 ± 48% over basal $IP_{n}$ accumulation in control cells and this value was significantly different (P < 0.04) from the 1 μm bradykinin-induced $IP_{n}$ accumulation in histamine-pretreated HeLa cells of 143 ± 38% over basal. 6 NaF stimulated $IP_{n}$ accumulation in control HeLa cells in a dose-related manner, with the maximum effect occurring at 15–20 mm. The $EC_{50}$ value for NaF-stimulated $IP_{n}$ accumulation in control cells was 10.5 ± 1.1 mm and the maximum response was 136 ± 41% over basal after 20 min incubation. In histamine desensitized HeLa cells the $EC_{50}$ value for NaF was 12.3 ± 0.4 mm after 20 min stimulation, which was not significantly different from the value obtained in control cells. The maximum NaF-stimulated $IP_{n}$ formation in desensitized cells of 68 ± 23% over basal occurred at 15–20 mm and was significantly lower (P < 0.01) than that obtained in control cells. 7 We show here that the acute histamine pretreatment of HeLa cells results in the desensitization of histamine $H_{1}$ receptor-mediated $IP_{n}$ production. The desensitization was not restricted to the $H_{1}$ receptor-mediated signal transduction pathway, but also includes both the bradykinin- and NaF-mediated responses, supporting a heterologous desensitization mechanism. Our results are consistent with the site of attenuation being at or distal to the G-protein and the underlying mechanism being a slowed time-course for the production of inositol phosphates.
Related Links	http://europepmc.org/articles/pmc2175704?pdf=render https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1476-5381.1993.tb13577.x
Ending Page	359
Page Count	7
Starting Page	353
e-ISSN	14765381
DOI	10.1111/j.1476-5381.1993.tb13577.x
Journal	British Journal of Pharmacology
Issue Number	2
Volume Number	109
Language	English
Publisher	Wiley-Blackwell
Publisher Date	1993-06-01
Access Restriction	Open
Subject Keyword	Journal: British Journal of Pharmacology Analytical Chemistry Histamine H1 Receptors Heterologous Desensitization Inositol Phosphates
Content Type	Text
Resource Type	Article