title: Regulation of the beta-receptor-adenylate cyclase system in lymphocytes of allergic patients with asthma: possible role for protein kinase C in allergen-induced nonspecific refractoriness of adenylate cyclase.
abstract: Allergen challenge of allergic patients with asthma caused various changes in the beta-receptor-adenylate cyclase system of lymphocyte membranes from these patients. These changes included uncoupling and down regulation of beta-adrenergic receptors and nonspecific refractoriness of adenylate cyclase, as demonstrated by reduced responses to isoproterenol (beta 2), histamine (H2), 5'-guanylylimidodiphosphate, and sodium fluoride. Since these changes could be due to desensitization by enhanced plasma levels of catecholamines and/or histamine during the allergic response, we explored the effects of these agonists on the beta-receptor-adenylate cyclase system in vitro with normal lymphocytes. In addition, we assessed the effect of the tumor-promoting phorbol ester, phorbol 12-myristate 13-acetate (PMA), on this system, since phorbol esters have been demonstrated to modulate several receptor systems, presumably via activation of protein kinase C. That both the agonists and PMA may cause refractoriness of lymphocyte adenylate cyclase was demonstrated, but, however, by apparently different mechanisms. The agonists isoproterenol and histamine induced only a specific desensitization of the homologous responses, whereas PMA-induced refractoriness was nonspecific in nature. Radioligand-binding studies demonstrated that both uncoupling and down regulation contributed to the isoproterenol-induced beta-adrenergic hyporesponsiveness, whereas beta-adrenergic receptor uncoupling but not beta-adrenergic receptor down regulation was involved in PMA-induced desensitization. Histamine had no effect on the beta-adrenergic system at all. The data suggest that the agonist-induced changes in the adenylate cyclase system are specifically located at the receptors, whereas PMA-induced refractoriness can be explained by alterations distal to the receptors, presumably at the stimulatory guanine nucleotide regulatory protein. Thus, enhanced levels of catecholamines or histamine could be involved in the development of receptor-specific changes in the lymphocyte adenylate cyclase system of allergic patients with asthma. However, they are unlikely to cause the nonspecific changes distal to the receptors. The latter changes could be induced by physiologic activation of protein kinase C during the allergic response by a still unknown stimulus, possibly via the receptor-mediated turnover of phosphatidylinositol 4,5-diphosphate.
mesh_terms: D020727:ADP-Ribosylation Factors; D000262:Adenylyl Cyclases / Q000097:blood*; D000328:Adult; D001249:Asthma / Q000097:blood* / Q000276:immunology; D001985:Bronchial Provocation Tests; D002352:Carrier Proteins; D004789:Enzyme Activation; D005260:Female; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008214:Lymphocytes / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000097:blood*; D011493:Protein Kinase C / Q000502:physiology; D011943:Receptors, Adrenergic, beta / Q000097:blood*; D012969:Sodium Fluoride / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; D011943:Receptors, Adrenergic, beta; D006165:Guanylyl Imidodiphosphate; D006632:Histamine; D012969:Sodium Fluoride; D011493:Protein Kinase C; D020727:ADP-Ribosylation Factors; D000262:Adenylyl Cyclases; D007545:Isoproterenol; D013755:Tetradecanoylphorbol Acetate