Studies on the receptor mediating cyclic AMP‐independent enhancement by adenosine of IgE‐dependent mediator release from rat mast cells

Abstract

1 Adenosine produced a concentration-related enhancement of antigen-induced 5-hydroxytryptamine (5-HT) release from rat serosal mast cells. This potentiation was maximal following the simultaneous addition of adenosine with antigen. 2 Enhancement of 5-HT release was accompanied by potentiation of the adenosine 3': 5'-cyclic monophosphate (cyclic AMP) response to challenge. The cyclic AMP response, which was antagonized by 8-phenyltheophylline, was characterized as an A2-purinoceptor-mediated effect by the use of 5'-N-ethylcarboxamideadenosine (NECA) and L-N6-phenylisopropyladenosine (L-PIA). 3 Enhancement of 5-HT release, conversely, was not blocked by 8-phenyltheophylline suggesting it to be mediated by a cyclic AMP-independent mechanism. 4 The effect of adenosine on 5-HT release was not reduced by the inhibition of the facilitated uptake of adenosine with dipyridamole, hexobendine or p-nitrobenzylthioguanosine, therefore, suggesting it to be mediated by a cell surface receptor. 5 The receptor mediating enhancement of 5-HT does not appear to belong to the P2-purinoceptor subtype as adenosine was more potent than both adenosine monophosphate (AMP) and adenosine diphosphate (ADP) and xB-methylene ATP was inactive. Furthermore, the effects of AMP were blocked by a,,B-methylene ADP, which inhibits the conversion of AMP to adenosine. 6 Adenosine, NECA, L-and D-PIA were all of equal potency in enhancing 5-HT release. Inosine and 3-deazaadenosine were also active. The rank order of potency of these adenosine analogues is not consistent with an effect at A,-or A2-purinoceptors. 7 There appear to be two adenosine receptors on rat mast cells, an A2-purinoceptor which stimulates adenylate cyclase and a separate purinoceptor, stimulation of which produces enhancement of mediator release by an unknown mechanism. The effects mediated by these receptors appear to be independent of each other.

Adenosine and inosine increase cutaneous vasopermeability by activating A3 receptors on mast cells

“…These findings are consistent with recent pharmacologic studies that showed inosine to preferentially bind to recombinant rat A 3 receptors (5). These studies also suggest that adenosine is more effective than inosine in mediating this response and are consistent with earlier studies with rat mast cells that showed inosine to be some 10 times less potent that adenosine at enhancing antigen-induced degranulation (46).…”

“…The biologic significance of these high tissue levels of inosine has not been established, nor is it known whether this metabolite mediates it actions solely by binding to adenosine receptors or whether it mediates its effects through yet undescribed inosine receptors. In vitro studies have shown that inosine can potentiate antigeninduced degranulation of both rat serosal mast cells and rat RBL-2H3 mastlike cells (5,46). We show here that inosine can also potentiate the degranulation of BMMCs.…”

Adenosine A2b receptors evoke interleukin-8 secretion in human mast cells. An enprofylline-sensitive mechanism with implications for asthma.

“…It was initially proposed that cAMP is involved in this process (5), but, at least in rat mast cells, the effect of adenosine on mediator release seems to be independent of cAMP (6). More recently, it has been shown that adenosine activates protein kinase C in mouse bone marrow-derived mast cells.…”

Synergistic effects of calcium‐mobilizing agents and adenosine on histamine release from rat peritoneal mast cells

“…The e histamine release appears to be enhanced sensitivity of the release l intracellular calcium (Lohse et almost no effect when the release is be total histamine content, but the same causes a more than half maximal enhW the release exceeds 40%. This dependence of the response to adenosine and its analogues on the level * of stimulation is a likely explanation for the large variations of its EC5o value and the flat concen-* tration-response curves when a large number of experiments are averaged, which has been found by various workers (Marquardt et al, 1978;Holgate et al, 1980;Welton & Simko 1980;Church et al, 1986). There are several reports in the literature that calcium may not alone be responsible for the mediation of secretory responses (see Gomperts, 1986, andPenner, 1988, for reviews).…”