Garbarg M, Schwartz J C
Unité 109 de Neurobiologie et Pharmacologie, Centre Paul Broca de l'INSERM, Paris, France.
Mol Pharmacol. 1988 Jan;33(1):38-43.
The synergism between H1- and H2-receptors in the histamine-induced stimulation of cAMP accumulation was studied in slices from guinea pig hippocampus. Since H1-receptors appear to be coupled to the phosphatidylinositol cycle, the participation of the two branches of the cycle in this synergism was assessed by using phorbol esters and/or by removing Ca2+ from the external medium. The protein kinase C activator, 4 beta-phorbol 12,13-dibutyrate (4 beta-PDB), strongly potentiated, with an EC50 of 0.2 microM, the accumulation of cAMP elicited by dimaprit, an H2-receptor agonist used at supramaximal concentration (0.3 mM). The effect of 4 beta-PDB was also observed in the presence of impromidine, an H2-receptor agonist, and histamine. 4 beta-Phorbol 12-myristate, 13-acetate, another protein kinase C activator, also potentiated the effect of dimaprit in a concentration-dependent manner although less potently than 4 beta-PDB. In contrast, 4 alpha-phorbol or the phorbol esters, 4 alpha-phorbol 12,13-didecanoate or 4-O-methylphorbol 12-myristate, 13-acetate, all inactive on protein kinase C, had no potentiating effect. 2-Thiazolylethylamine (2-TEA), a predominantly H1-receptor agonist, increased the stimulation induced by dimaprit (0.3 mM), and this response was further enhanced in the presence of 4 beta-PDB in maximal concentration (1 microM). Mepyramine (0.1 microM) antagonized the H1-receptor-mediated effect in the absence as well as the presence of 4 beta-PDB. The phorbol ester did not significantly alter the EC50 of 2-TEA or the magnitude of its effect. In the absence of phorbol esters, removal of Ca2+ from the incubation medium did not change the response elicited by 0.3 mM dimaprit but reduced by 50% the response to a supramaximal concentration of 2-TEA. This effect was more marked when EGTA was added in the Ca2+-free medium. The EC50 value of 2-TEA was only slightly modified in the absence of Ca2+ (180 +/- 20 microM as compared with 70 +/- 4 microM in the presence of 2.6 mM Ca2+). In the presence of 4 beta-PDB (1 microM), removal of Ca2+, particularly in the presence of EGTA, did not affect or slightly increased the response to dimaprit, but still strongly reduced the response to 2-TEA. The Ca2+ ionophore A 23187 (10 microM) showed a tendency to mimic the potentiating effect of 2-TEA.(ABSTRACT TRUNCATED AT 400 WORDS)
在豚鼠海马切片中研究了组胺诱导的环磷酸腺苷（cAMP）积累过程中H1和H2受体之间的协同作用。由于H1受体似乎与磷脂酰肌醇循环相偶联，因此通过使用佛波酯和/或从细胞外培养基中去除Ca2+来评估该循环的两个分支在这种协同作用中的参与情况。蛋白激酶C激活剂4β-佛波醇12,13-二丁酸酯（4β-PDB）以0.2微摩尔的半数有效浓度（EC50）强烈增强了由地马普明（一种以超最大浓度0.3毫摩尔使用的H2受体激动剂）引起的cAMP积累。在存在H2受体激动剂英普咪定和组胺的情况下也观察到了4β-PDB的作用。另一种蛋白激酶C激活剂4β-佛波醇12-肉豆蔻酸酯13-乙酸酯也以浓度依赖的方式增强了地马普明的作用，尽管效力不如4β-PDB。相反，对蛋白激酶C无活性的4α-佛波醇或佛波酯4α-佛波醇12,13-十二烷酸酯或4-O-甲基佛波醇12-肉豆蔻酸酯13-乙酸酯没有增强作用。2-噻唑基乙胺（2-TEA），一种主要的H1受体激动剂，增加了由地马普明（0.3毫摩尔）诱导的刺激，并且在存在最大浓度（1微摩尔）的4β-PDB时这种反应进一步增强。在不存在和存在4β-PDB的情况下，美吡拉敏（0.1微摩尔）均拮抗H1受体介导的作用。佛波酯没有显著改变2-TEA的EC50或其作用强度。在不存在佛波酯的情况下，从孵育培养基中去除Ca2+并没有改变由0.3毫摩尔地马普明引起的反应，但将对超最大浓度2-TEA的反应降低了50%。当在无Ca2+培养基中加入乙二醇双四乙酸（EGTA）时，这种作用更明显。在不存在Ca2+的情况下，2-TEA的EC50值仅略有改变（与存在2.6毫摩尔Ca2+时的70±4微摩尔相比为180±20微摩尔）。在存在4β-PDB（1微摩尔）的情况下，去除Ca2+，特别是在存在EGTA的情况下，并不影响或略微增加对地马普明的反应，但仍然强烈降低对2-TEA的反应。Ca2+离子载体A 23187（10微摩尔）显示出模拟2-TEA增强作用的趋势。（摘要截短至400字）
