Abstract
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)
MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|