Occupancy of adenosine receptors raised cyclic AMP alone and in synergy with occupancy of chemoattractant receptors and inhibits membrane depolarization

B. N. Cronstein, S. B. Kramer, Elliot Rosenstein, H. M. Korchak, G. Weissmann, R. Hirschhorn

Research output: Contribution to journalArticle

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Abstract

We have recently demonstrated that adenosine, acting via adenosine A2 receptors, inhibits generation of superoxide anions (O2 -) by stimulated neutrophils. To determine the mechanism(s) by which adenosine inhibits O2 - generation stimulated by the chemoattractant N-formylmethionylleucylphenylalanine (FMLP), we examined cyclic AMP (cAMP) concentrations, stimulated membrane depolarization and Ca2+ movements. Neither adenosine nor 5'-N-ethylcarboxamidoadenosine (NECA), the most potent agonist at adenosine A2 receptors, increases neutrophil cAMP content. However in the presence of the non-methylxanthine phosphodiesterase inhibitor, PO-20-1724, both adenosine and NECA elicit a reversible increase in intracellular cAMP concentration. The chemoattractant FMLP also elicits an increment in the neutrophil cAMP content. NECA, in the presence of Ro-20-1724, synergistically enhances the increment in cAMP following stimulation by FMLP. However Ro-20-1724 does not potentiate the inhibition of O2 - generation by NECA. Unlike other agents which increase neutrophil cAMP concentrations, NECA, even in the presence of a phosphodiesterase inhibitor, only trivially inhibits degranulation. We also found that adenosie markedly inhibits stimulated membrane depolarization but does not affect the stimulated increment in free ionized intracellular calcium. Moreover, inhibition by adenosine of O2 - generation does not vary with the concentration of extracellular calcium. These results fulfil the last criterion for the demonstration of an A2 receptor on human neutrophils, and indicate that adenosine occupies and A2 receptor on neutrophils to raise intracellular cAMP in synergy with occupancy of the FMLP receptor. The results reported here also indicate that cAMP in not the second messenger for inhibition of O2 - generation by adenosine and its analogues.

Original languageEnglish (US)
Pages (from-to)709-715
Number of pages7
JournalBiochemical Journal
Volume252
Issue number3
DOIs
StatePublished - Jan 1 1988

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Formyl Peptide Receptor
Purinergic P1 Receptors
Depolarization
Cyclic AMP
Adenosine-5'-(N-ethylcarboxamide)
Adenosine
Membranes
N-Formylmethionine Leucyl-Phenylalanine
Neutrophils
Adenosine A2 Receptors
4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone
Phosphodiesterase Inhibitors
Chemotactic Factors
Adenosine A2 Receptor Agonists
Calcium
Second Messenger Systems
varespladib methyl
Superoxides
Demonstrations

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Cronstein, B. N. ; Kramer, S. B. ; Rosenstein, Elliot ; Korchak, H. M. ; Weissmann, G. ; Hirschhorn, R. / Occupancy of adenosine receptors raised cyclic AMP alone and in synergy with occupancy of chemoattractant receptors and inhibits membrane depolarization. In: Biochemical Journal. 1988 ; Vol. 252, No. 3. pp. 709-715.
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Occupancy of adenosine receptors raised cyclic AMP alone and in synergy with occupancy of chemoattractant receptors and inhibits membrane depolarization. / Cronstein, B. N.; Kramer, S. B.; Rosenstein, Elliot; Korchak, H. M.; Weissmann, G.; Hirschhorn, R.

In: Biochemical Journal, Vol. 252, No. 3, 01.01.1988, p. 709-715.

Research output: Contribution to journalArticle

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T1 - Occupancy of adenosine receptors raised cyclic AMP alone and in synergy with occupancy of chemoattractant receptors and inhibits membrane depolarization

AU - Cronstein, B. N.

AU - Kramer, S. B.

AU - Rosenstein, Elliot

AU - Korchak, H. M.

AU - Weissmann, G.

AU - Hirschhorn, R.

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N2 - We have recently demonstrated that adenosine, acting via adenosine A2 receptors, inhibits generation of superoxide anions (O2 -) by stimulated neutrophils. To determine the mechanism(s) by which adenosine inhibits O2 - generation stimulated by the chemoattractant N-formylmethionylleucylphenylalanine (FMLP), we examined cyclic AMP (cAMP) concentrations, stimulated membrane depolarization and Ca2+ movements. Neither adenosine nor 5'-N-ethylcarboxamidoadenosine (NECA), the most potent agonist at adenosine A2 receptors, increases neutrophil cAMP content. However in the presence of the non-methylxanthine phosphodiesterase inhibitor, PO-20-1724, both adenosine and NECA elicit a reversible increase in intracellular cAMP concentration. The chemoattractant FMLP also elicits an increment in the neutrophil cAMP content. NECA, in the presence of Ro-20-1724, synergistically enhances the increment in cAMP following stimulation by FMLP. However Ro-20-1724 does not potentiate the inhibition of O2 - generation by NECA. Unlike other agents which increase neutrophil cAMP concentrations, NECA, even in the presence of a phosphodiesterase inhibitor, only trivially inhibits degranulation. We also found that adenosie markedly inhibits stimulated membrane depolarization but does not affect the stimulated increment in free ionized intracellular calcium. Moreover, inhibition by adenosine of O2 - generation does not vary with the concentration of extracellular calcium. These results fulfil the last criterion for the demonstration of an A2 receptor on human neutrophils, and indicate that adenosine occupies and A2 receptor on neutrophils to raise intracellular cAMP in synergy with occupancy of the FMLP receptor. The results reported here also indicate that cAMP in not the second messenger for inhibition of O2 - generation by adenosine and its analogues.

AB - We have recently demonstrated that adenosine, acting via adenosine A2 receptors, inhibits generation of superoxide anions (O2 -) by stimulated neutrophils. To determine the mechanism(s) by which adenosine inhibits O2 - generation stimulated by the chemoattractant N-formylmethionylleucylphenylalanine (FMLP), we examined cyclic AMP (cAMP) concentrations, stimulated membrane depolarization and Ca2+ movements. Neither adenosine nor 5'-N-ethylcarboxamidoadenosine (NECA), the most potent agonist at adenosine A2 receptors, increases neutrophil cAMP content. However in the presence of the non-methylxanthine phosphodiesterase inhibitor, PO-20-1724, both adenosine and NECA elicit a reversible increase in intracellular cAMP concentration. The chemoattractant FMLP also elicits an increment in the neutrophil cAMP content. NECA, in the presence of Ro-20-1724, synergistically enhances the increment in cAMP following stimulation by FMLP. However Ro-20-1724 does not potentiate the inhibition of O2 - generation by NECA. Unlike other agents which increase neutrophil cAMP concentrations, NECA, even in the presence of a phosphodiesterase inhibitor, only trivially inhibits degranulation. We also found that adenosie markedly inhibits stimulated membrane depolarization but does not affect the stimulated increment in free ionized intracellular calcium. Moreover, inhibition by adenosine of O2 - generation does not vary with the concentration of extracellular calcium. These results fulfil the last criterion for the demonstration of an A2 receptor on human neutrophils, and indicate that adenosine occupies and A2 receptor on neutrophils to raise intracellular cAMP in synergy with occupancy of the FMLP receptor. The results reported here also indicate that cAMP in not the second messenger for inhibition of O2 - generation by adenosine and its analogues.

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