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Expression of fibrinogen receptors during activation and subsequent
desensitization of human platelets by epinephrine
SJ Shattil, HJ Motulsky, PA Insel, L Flaherty and LF Brass
Epinephrine causes platelet aggregation and secretion by interacting with
alpha 2-adrenergic receptors on the platelet surface. Platelet aggregation
requires the binding of fibrinogen to a specific receptor on the membrane
glycoprotein IIb-IIIa complex. Although the IIb-IIIa complex is
identifiable on the surface of resting platelets, the fibrinogen receptor
is expressed only after platelet activation. The current studies were
designed to examine the effect of occupancy of platelet alpha 2-adrenergic
receptors by epinephrine on the expression of fibrinogen receptors and on
the aggregation of platelets. The ability of epinephrine to induce the
expression of fibrinogen receptors was studied under two different
conditions: acute stimulation (less than 1 min) and prolonged stimulation
(50 to 90 min), the latter of which is associated with a reduction or
"desensitization" of the platelet aggregation response. Expression of the
fibrinogen receptor was monitored with 125I-fibrinogen as well as with
125I-PAC-1 (PAC-1), a monoclonal antibody that binds to the glycoprotein
IIb-IIIa complex only after platelets are activated. Epinephrine caused an
immediate increase in PAC-1 and fibrinogen binding that was dependent on
occupancy of the alpha 2-receptor by epinephrine and on the presence of
extracellular free Ca (KCa = 30 mumol/L). By itself, 1 mmol/L Mg was unable
to support induction of the fibrinogen receptor by epinephrine. However, it
did decrease the Ca requirement by about two orders of magnitude. Prolonged
stimulation of unstirred platelets by epinephrine led to a 70% decrease in
the aggregation response when the platelets were subsequently stirred.
Despite their decreased aggregation response, desensitized platelets bound
PAC-1 and fibrinogen normally, indicating that the loss of aggregation was
not due simply to a decrease in fibrinogen receptor expression. Although
desensitization was not affected by pretreatment of the platelets with
aspirin, it was partially prevented when extracellular Ca was chelated by
EDTA during the long incubation with epinephrine. These studies demonstrate
that once platelet alpha 2-adrenergic receptors are occupied by
epinephrine, extracellular Ca is involved in initiating the aggregation
response by supporting the induction of the fibrinogen receptor and the
binding of fibrinogen. Furthermore. Ca-dependent reactions subsequent to
fibrinogen binding may be necessary for maximal platelet aggregation and
are impaired when platelets become desensitized to epinephrine.
Volume 68,
Issue 6,
pp. 1224-1231,
12/01/1986
Copyright © 1986 by The American Society of Hematology
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