|
|
 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 10 (November 15), 1998:
pp. 3675-3683
Association Between Ligand-Induced Conformational Changes of Integrin
 IIb 3 and
IIb3-Mediated Intracellular
Ca2+ Signaling
Shigenori Honda,
Yoshiaki Tomiyama,
Toshiaki Aoki,
Masamichi Shiraga,
Yoshiyuki Kurata,
Jiro Seki, and
Yuji Matsuzawa
From The Second Department of Internal Medicine, Osaka University
Medical School, Osaka, Japan; the New Drug Research Laboratory,
Fujisawa Pharmaceutical Co, Ltd, Osaka, Japan; and the
Department of Blood Transfusion, Osaka University Hospital,
Osaka, Japan.
Platelet  IIb 3 is a prototypic integrin
and plays a critical role in platelet aggregation. Occupancy of
IIb3 with multivalent RGD ligands, such
as fibrinogen, induces both expression of ligand-induced binding sites
(LIBS) and IIb3 clustering, which are
thought to be necessary for outside-in signaling. However, the
association between LIBS expression and outside-in signaling remains
elusive. In this study, we used various
IIb3-specific peptidomimetic compounds as
a monovalent ligand instead of fibrinogen and examined the association
between LIBS expression and outside-in signaling such as
IIb3-mediated intracellular
Ca2+ signaling. Using a set of monoclonal antibodies
(MoAbs) against LIBS, we showed that antagonists can be divided into
two groups. In group I, antagonists can induce LIBS on both
IIb and 3 subunits. In group II,
antagonists can induce LIBS on the IIb subunit, but not
on the 3 subunit. Inhibition studies suggested that
group I and group II antagonists interact with distinct but mutually exclusive sites on IIb3. Neither group I
nor group II antagonist increased intracellular Ca2+
concentrations ([Ca2+]i) in nonactivated
platelets. All antagonists at nanomolar concentrations abolished the
increase in [Ca2+]i in 0.03 U/mL
thrombin-stimulated platelets, which is dependent on both
fibrinogen-binding to IIb3 and
platelet-aggregation. However, only group I antagonists at higher
concentrations dose-dependently augmented the
[Ca2+]i increase, which is due to
aggregation-independent thromboxane A2 production. This
increase in [Ca2+]i was not observed in
thrombasthenic platelets, which express no detectable
IIb3. Thus, only the group I antagonists,
albeit a monovalent ligand, can initiate
IIb3-mediated intracellular Ca2+ signaling in the presence of thrombin stimulation.
Our findings strongly suggest the association between 3
LIBS expression and IIb3-mediated
intracellular Ca2+ signaling in platelets.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
R. Blue, M. Murcia, C. Karan, M. Jirouskova, and B. S. Coller
Application of high-throughput screening to identify a novel {alpha}IIb-specific small- molecule inhibitor of {alpha}IIb{beta}3-mediated platelet interaction with fibrinogen
Blood,
February 1, 2008;
111(3):
1248 - 1256.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. Beau Mitchell, J. Li, M. Murcia, N. Valentin, P. J. Newman, and B. S. Coller
Mapping early conformational changes in {alpha}IIb and {beta}3 during biogenesis reveals a potential mechanism for {alpha}IIb{beta}3 adopting its bent conformation
Blood,
May 1, 2007;
109(9):
3725 - 3732.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. R. Van de Walle, A. Schoolmeester, B. F. Iserbyt, J. M. E. M. Cosemans, J. W. M. Heemskerk, M. F. Hoylaerts, A. Nurden, K. Vanhoorelbeke, and H. Deckmyn
Activation of {alpha}IIb{beta}3 is a sufficient but also an imperative prerequisite for activation of {alpha}2{beta}1 on platelets
Blood,
January 15, 2007;
109(2):
595 - 602.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W.-Y. Wang, Y.-C. Wu, and C.-C. Wu
Prevention of Platelet Glycoprotein IIb/IIIa Activation by 3,4-Methylenedioxy-beta-Nitrostyrene, A Novel Tyrosine Kinase Inhibitor
Mol. Pharmacol.,
October 1, 2006;
70(4):
1380 - 1389.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Kashiwagi, M. Shiraga, H. Kato, T. Kamae, N. Yamamoto, S. Tadokoro, Y. Kurata, Y. Tomiyama, and Y. Kanakura
Negative regulation of platelet function by a secreted cell repulsive protein, semaphorin 3A
Blood,
August 1, 2005;
106(3):
913 - 921.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. H. Aster
Immune Thrombocytopenia Caused by Glycoprotein IIb/IIIa Inhibitors
Chest,
February 1, 2005;
127(2_suppl):
53S - 59S.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Schwarz, Y. Katagiri, M. Kotani, N. Bassler, C. Loeffler, C. Bode, and K. Peter
Reversibility versus Persistence of GPIIb/IIIa Blocker-Induced Conformational Change of GPIIb/IIIa ({alpha}IIb{beta}3, CD41/CD61)
J. Pharmacol. Exp. Ther.,
March 1, 2004;
308(3):
1002 - 1011.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Dalby, G. Montalescot, C. B. d. Sollier, E. Vicaut, T. Soulat, J.-P. Collet, R. Choussat, V. Gallois, G. Drobinski, L. Drouet, et al.
Eptifibatide provides additional platelet inhibition in Non-ST-Elevation myocardial infarction patients already treated with aspirin and clopidogrel: Results of the platelet activity extinction in Non-Q-Wave myocardial infarction with aspirin, clopidogrel, and eptifibatide (PEACE) study
J. Am. Coll. Cardiol.,
January 21, 2004;
43(2):
162 - 168.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. J. Quinn, T. V. Byzova, J. Qin, E. J. Topol, and E. F. Plow
Integrin {alpha}IIb{beta}3 and Its Antagonism
Arterioscler. Thromb. Vasc. Biol.,
June 1, 2003;
23(6):
945 - 952.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Kiyoi, Y. Tomiyama, S. Honda, S. Tadokoro, M. Arai, H. Kashiwagi, S. Kosugi, H. Kato, Y. Kurata, and Y. Matsuzawa
A naturally occurring Tyr143Hisalpha IIb mutation abolishes alpha IIbbeta 3 function for soluble ligands but retains its ability for mediating cell adhesion and clot retraction: comparison with other mutations causing ligand-binding defects
Blood,
May 1, 2003;
101(9):
3485 - 3491.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. W. Bougie, P. R. Wilker, E. D. Wuitschick, B. R. Curtis, M. Malik, S. Levine, R. N. Lind, J. Pereira, and R. H. Aster
Acute thrombocytopenia after treatment with tirofiban or eptifibatide is associated with antibodies specific for ligand-occupied GPIIb/IIIa
Blood,
August 28, 2002;
100(6):
2071 - 2076.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. J. Quinn, E. F. Plow, and E. J. Topol
Platelet Glycoprotein IIb/IIIa Inhibitors: Recognition of a Two-Edged Sword?
Circulation,
July 16, 2002;
106(3):
379 - 385.
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Peter, M. Schwarz, C. Bode, A. L. Frelinger III, M. I. Furman, L. A. Krueger, M. R. Barnard, and A. D. Michelson
Activating Effects of GPIIb/IIIa Blockers: An Intrinsic Consequence of Ligand- Mimetic Properties * Response
Circulation,
May 28, 2002;
105
(21):
e180 - e181.
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Tadokoro, Y. Tomiyama, S. Honda, H. Kashiwagi, S. Kosugi, M. Shiraga, T. Kiyoi, Y. Kurata, and Y. Matsuzawa
Missense mutations in the beta 3 subunit have a different impact on the expression and function between alpha IIbbeta 3 and alpha vbeta 3
Blood,
February 1, 2002;
99(3):
931 - 938.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. F. O'Connor, D. C. Shields, A. Fitzgerald, C. P. Cannon, E. Braunwald, and D. J. Fitzgerald
Genetic variation in glycoprotein IIb/IIIa (GPIIb/IIIa) as a determinant of the responses to an oral GPIIb/IIIa antagonist in patients with unstable coronary syndromes
Blood,
December 1, 2001;
98(12):
3256 - 3260.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Kosugi, Y. Tomiyama, S. Honda, H. Kato, T. Kiyoi, H. Kashiwagi, Y. Kurata, and Y. Matsuzawa
Platelet-associated anti-GPIIb-IIIa autoantibodies in chronic immune thrombocytopenic purpura recognizing epitopes close to the ligand-binding site of glycoprotein (GP) IIb
Blood,
September 15, 2001;
98(6):
1819 - 1827.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. I. Lev, J. I. Osende, M. F. Richard, J. A. Robbins, J. A. Delfin, O. Rodriguez, S. K. Sharma, T. Jayasundera, J. J. Badimon, and J. D. Marmur
Administration of abciximab to patients receiving tirofiban or eptifibatide: effect on platelet function
J. Am. Coll. Cardiol.,
March 1, 2001;
37(3):
847 - 855.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Honda, Y. Tomiyama, N. Pampori, H. Kashiwagi, T. Kiyoi, S. Kosugi, S. Tadokoro, Y. Kurata, S. J. Shattil, and Y. Matsuzawa
Ligand binding to integrin {alpha}v{beta}3 requires tyrosine 178 in the {alpha}v subunit
Blood,
January 1, 2001;
97(1):
175 - 182.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Curtin and D.J. Fitzgerald
A cold start for oral glycoprotein IIb/IIIa antagonists
Eur. Heart J.,
December 2, 2000;
21(24):
1992 - 1994.
[PDF]
|
|
|
|
|
|
|
D. Cox, R. Smith, M. Quinn, P. Theroux, P. Crean, and D. J. Fitzgerald
Evidence of platelet activation during treatment with a GPIIb/IIIa antagonist in patients presenting with acute coronary syndromes
J. Am. Coll. Cardiol.,
November 1, 2000;
36(5):
1514 - 1519.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. J. Quinn, D. Cox, J. B. Foley, and D. J. Fitzgerald
Glycoprotein IIb/IIIa Receptor Number and Occupancy during Chronic Administration of an Oral Antagonist
J. Pharmacol. Exp. Ther.,
November 1, 2000;
295(2):
670 - 676.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
R. M. Scarborough, N. S. Kleiman, and D. R. Phillips
Platelet Glycoprotein IIb/IIIa Antagonists : What Are the Relevant Issues Concerning Their Pharmacology and Clinical Use?
Circulation,
July 27, 1999;
100(4):
437 - 444.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Kashiwagi, Y. Tomiyama, S. Tadokoro, S. Honda, M. Shiraga, H. Mizutani, M. Handa, Y. Kurata, Y. Matsuzawa, and S. J. Shattil
A Mutation in the Extracellular Cysteine-Rich Repeat Region of the beta 3 Subunit Activates Integrins alpha IIbbeta 3 and alpha Vbeta 3
Blood,
April 15, 1999;
93(8):
2559 - 2568.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
