Defect in potentiation of adenylyl cyclase correlates with bronchial hyperreactivity.
BACKGROUND
Adenylyl cyclase is a transmembrane signaling system involved in the inhibition of cellular responses. Recently, we showed that the activity of adenylyl cyclase may be potentiated by stimuli that induce an increase of cellular responses but that do not activate adenylyl cyclase. This is probably an important physiologic feedback mechanism that prevents cells from becoming "overstimulated."


OBJECTIVE
Because increased cellular activities are frequently observed in persons with asthma, we hypothesized that a defect in potentiation of adenylyl cyclase might be involved.


METHODS
Potentiation of isoprenaline-induced adenosine cyclic monophosphate (cAMP) production with the mitogen phytohemagglutin (PHA; 45 micrograms/ml) or the calcium ionophore A23187 (1 mumol/L) was studied in peripheral blood mononuclear cells taken from patients with asthma (n = 8) and healthy control subjects (n = 11).


RESULTS
Isoprenaline-induced cAMP production was potentiated significantly in the healthy control subjects (PHA, 110% +/- 15%; A23187, 92% +/- 25%). In contrast, potentiation was not seen with PHA or A23187 in the total group of patients with asthma. However, some patients showed weak potentiation, whereas in others PHA decreased isoprenaline-induced cAMP production. Moreover, the effect of PHA on isoprenaline-induced cAMP production correlated significantly with the degree of bronchial hyperreactivity in patients with asthma (r = 0.96; p = 0.0001).


CONCLUSIONS
The observed defect in signal transduction could play an important part in bronchial hyperresponsiveness.
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000328:Adult; D001249:Asthma / Q000150:complications / Q000201:enzymology; D016535:Bronchial Hyperreactivity / Q000150:complications / Q000201:enzymology*; D001985:Bronchial Provocation Tests; D001993:Bronchodilator Agents / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007476:Ionophores / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000201:enzymology; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D010835:Phytohemagglutinins / Q000494:pharmacology; D015398:Signal Transduction
D001993:Bronchodilator Agents; D007476:Ionophores; D010835:Phytohemagglutinins; D016210:Methacholine Chloride; D000001:Calcimycin; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D007545:Isoproterenol