No abstract

1 Histamine stimulated the accumulation of total [3H]-inositol phosphates (IPn) in control HeLa cells with an EC50 of 3.7 ± 0.7 JAM 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 IPX, production in HeLa cells was confirmed as H, receptor-mediated, since the H, antagonist mepyramine (10-6 M) inhibited the histamine response (10-4 M) by 83 ± 7%, whereas the H2 antagonist, ranitidine (10-4M), and H3 antagonist, thioperamide (10-6M), were ineffective. 3 Histamine (10-M) pretreatment of HeLa cells for 30 min desensitized the subsequent histamineinduced IP,, accumulation. The desensitized cells accumulated IP. in response to histamine with an EC50 of 1.7 ± 0.7 JAM after 15 min incubation. The maximum histamine-induced IP,, accumulation at I0-4 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,, 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,, 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,, accumulation in HeLa cells, and the ECm in control cells of 1.9 ± 0.2 nM was not significantly different from the EC50 value from histamine-pretreated cells of 1.6 ± 0.9 nM. The bradykinin response at 1 ILM was 194 ± 48% over basal IP,, accumulation in control cells and this value was significantly different (P <0.04) from the 1 JAM bradykinin-induced IP,, accumulation in histaminepretreated HeLa cells of 143 ± 38% over basal. 6 NaF stimulated IP,, accumulation in control HeLa cells in a dose-related manner, with the maximum effect occurring at 15-20 mM. The ECm value for NaF-stimulated IP,, 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 EC50 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 NaFstimulated IP,, 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, receptor-mediated IP,, production. The desensitization was not restricted to the H, receptor-mediated signal transduction pathway, but also includes both the bradykinin-and NaFmediated responses, supporting a heterologous desensitization mechanism. Our results are consistent with the si...

Fluctuating estradiol levels in the adult, female rat modify the anatomical and functional organization of the hippocampal CA1 region. When systemic levels of estradiol are low, e.g., on estrus or in ovariectomized (OVX) rats, long-term synaptic potentiation is difficult to induce in vivo. However, little is known about the role of this ovarian hormone in long-term synaptic depression. Using multiple conditioning paradigms, we assess the magnitude of long-term depression (LTD) at CA3-CA1 synapses in vitro from adult, ovariectomized rats as a function of systemic estradiol replacement. In hippocampal slices from control OVX rats with low levels of estradiol, a low-frequency (2 Hz), asynchronous conditioning stimulation protocol does not produce LTD at 1 h postconditioning. However, this same protocol induces robust LTD in slices from estradiol-treated OVX rats. When the conditioning frequency is increased to 4 Hz, slices from both groups of rats show robust LTD in vitro. At an even higher conditioning frequency (10 Hz), the 2-Hz-based observations are reversed; no consistent changes in synaptic transmission are observed in slices from estradiol-treated OVX rats, but those from control rats (OVX + oil) show robust LTD. Thus estradiol reduces the frequency threshold for LTD induction at the CA3-CA1 synapses. Further, regardless of the conditioning frequency employed, where robust LTD is seen, its induction depends on normally functioning N-methyl-D-aspartate (NMDA) receptors during conditioning. The shift in conditioning frequency needed to elicit LTD is consistent with a decrease in NMDA receptor activation with decreasing estradiol levels.

No abstract