SYNERGISM BETWEEN HISTAMINE H-1-RECEPTOR AND H-2-RECEPTOR IN THE CAMP RESPONSE IN GUINEA-PIG BRAIN-SLICES - EFFECTS OF PHORBOL ESTERS AND CALCIUM

  • 1 January 1988
    • journal article
    • research article
    • Vol. 33  (1) , 38-43
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 .mu.M, the accumulation of cAMP elicited by dimaprit, and 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 protentiated 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-didecanotate or 4-O-methyl-phorbol 12-myristate, 13-acetate, all inactive on protein kinase C, had no potentiating effect. 2-Thiazolyethylamine (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 .mu.M). Mepyramine (0.1 .mu.M) 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 .mu.M as compared with 70 .+-. 4 .mu.M in the presence of 2.6 mM Ca2+). In the presence of 4.beta.-PDB (1 .mu.M), 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 .mu.M) showed a tendency to mimic the potentiating effect of 2-TEA. The present data do not rule out a participation of protein kinase C in the synergistic response triggered by H1-receptor stimulation but suggest a major participation of external Ca2+, possibly mediated by inositol phosphates.