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Occupancy of G alpha s-linked receptors uncouples chemoattractant receptors
from their stimulus-transduction mechanisms in the neutrophil
BN Cronstein, KA Haines, S Kolasinski and J Reibman
Department of Medicine, New York University Medical Center, NY 10016.
Adenosine and adrenergic agonists modulate neutrophil function by ligating
their specific receptors (adenosine A2 and beta-adrenergic) on the
neutrophil. When occupied, adenosine A2 and beta-adrenergic receptors
stimulate, presumably via G alpha s, an increase in intracellular 3', 5'
cyclic adenosine monophosphate (cAMP). cAMP affects cellular functions, in
part, via protein kinase-mediated phosphorylation. Therefore, we determined
whether inhibition of protein kinase A activity by KT5720 (10 mumol/L)
reversed the inhibition of FMLP-stimulated O2- generation by
5'N-ethylcarboxamidoadenosine (NECA), the most potent adenosine A2 agonist,
and by isoproterenol a potent beta-adrenergic agonist. KT5720 did not
affect O2- generation stimulated by FMLP (125% +/- 13% of control, n = 5).
However, KT5720 completely reversed inhibition of O2- generation by
dibutyryl cAMP (DbcAMP, 1 mmol/L, from 26% +/- 5% to 84% +/- 25% of
control, n = 5, P less than .004), but not by NECA (1 mumol/L, 26% +/- 5% v
33% +/- 7% of control, n = 5) or isoproterenol (10 mumol/L, 20% +/- 8% to
38% +/- 6% of control, n = 5). Nearly identical results were obtained using
the less specific protein kinase inhibitor H-7. To determine whether
occupancy of adenosine A2 or beta-adrenergic receptors inhibits neutrophil
(PMN) activation by uncoupling chemoattractant receptors from G proteins,
we determined the effect of NECA and isoproterenol on guanosine
triphosphatase (GTPase) activity, a parameter that reflects G protein
"activation," of plasma membranes derived from human PMNs. Control GTPase
activity was 138.9 pmol/mg protein/min; NECA (1 nmol/L to 1 mumol/L) and
isoproterenol (10 nmol/L to 10 mumol/L) alone did not significantly affect
GTPase activity. FMLP (0.1 mumol/L) increased GTPase activity by 31.9 +/-
.9 pmol/mg/min, an increment that was markedly inhibited to approximately
50% of control by NECA (IC50 = 3 nmol/L, P less than .001, n = 5) and
isoproterenol (IC50 = 30 nmol/L, P less than .001, n = 5). Neither cAMP nor
dibutyryl cAMP (10 mumol/L and 1 mmol/L) affected resting or stimulated
GTPase activity. In addition, neither adenosine nor DbcAMP affected protein
phosphorylation in resting or stimulated neutrophils. Our studies are
consistent with the hypothesis that ligation of G alpha s-linked receptors
uncouples chemoattractant receptors from their signal-transduction
mechanisms rather than inhibiting neutrophil function via cAMP-mediated
effects.
Volume 80,
Issue 4,
pp. 1052-1057,
08/15/1992
Copyright © 1992 by The American Society of Hematology
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