Enzymatic regulation of mast cell activation and secretion by adenylate cyclase and cyclic AMP-dependent protein kinases.
This review details the biochemical events that follow IgE dimerization by antigen and cross-linking of receptors and are linked with the early rise in cyclic AMP. That the monophasic rise in cyclic AMP at 15 s is essential to the degranulation process is evident by pharmacological manipulation of adenylate cyclase, using specific activators and inhibitors to achieve potentiation and inhibition of immunologic release, respectively. Although only a small percentage of membrane adenylate cyclase is transmembrane linked to IgE-Fc perturbation, its product, cyclic AMP, is elevated during activation and is responsible for the activation of two protein kinase isoenzymes at 30-60 s. This sequence appears to be essential for secretion to occur, as evidenced by dose-related inhibition of both beta-hexosaminidase release and protein kinase activation by adenylate cyclase inhibitors. Competitive activation of cyclic AMP-dependent protein kinase activity by a phosphodiesterase inhibitor leads to inhibition of mediator release by diverting an essential enzyme or recruiting an inhibitory sequence. The precise functional role of the mast cell cyclic AMP-dependent protein kinases has not yet been identified, but there is much evidence in other cell types that protein phosphorylation is an essential accompaniment to cellular regulation. Although other apparently essential biochemical steps are noted, such as uncovering a serine esterase, methylation of membrane phospholipid, and increased Ca2+ influx, only a portion of the activation-secretion response is presented here as a sequence, namely, the IgE-Fc receptor-initiated, transmembrane-coupled activation of adenylate cyclase and the subsequent cytoplasmic cyclic AMP-dependent activation of types I and II protein kinases.
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism*; D006168:Guinea Pigs; D006636:Histamine Release; D007073:Immunoglobulin E; D008407:Mast Cells / Q000502:physiology*; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D017455:Receptors, IgE; D011971:Receptors, Immunologic
D017455:Receptors, IgE; D011971:Receptors, Immunologic; D007073:Immunoglobulin E; D000242:Cyclic AMP; D011494:Protein Kinases; D000262:Adenylyl Cyclases