Linked Life Data

9808561

Source:http://linkedlifedata.com/resource/pubmed/id/9808561

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
10
pubmed:dateCreated
1998-12-21
pubmed:abstractText
Platelet IIbbeta3 is a prototypic integrin and plays a critical role in platelet aggregation. Occupancy of IIbbeta3 with multivalent RGD ligands, such as fibrinogen, induces both expression of ligand-induced binding sites (LIBS) and IIbbeta3 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 IIbbeta3-specific peptidomimetic compounds as a monovalent ligand instead of fibrinogen and examined the association between LIBS expression and outside-in signaling such as IIbbeta3-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 beta3 subunits. In group II, antagonists can induce LIBS on the IIb subunit, but not on the beta3 subunit. Inhibition studies suggested that group I and group II antagonists interact with distinct but mutually exclusive sites on IIbbeta3. 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 IIbbeta3 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 IIbbeta3. Thus, only the group I antagonists, albeit a monovalent ligand, can initiate IIbbeta3-mediated intracellular Ca2+ signaling in the presence of thrombin stimulation. Our findings strongly suggest the association between beta3 LIBS expression and IIbbeta3-mediated intracellular Ca2+ signaling in platelets.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
AIM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/((4-(4-amidinophenoxy)butanoyl)aspar..., http://linkedlifedata.com/resource/pubmed/chemical/Acetates, http://linkedlifedata.com/resource/pubmed/chemical/Antibodies, Monoclonal, http://linkedlifedata.com/resource/pubmed/chemical/Benzamidines, http://linkedlifedata.com/resource/pubmed/chemical/Dipeptides, http://linkedlifedata.com/resource/pubmed/chemical/Piperidines, http://linkedlifedata.com/resource/pubmed/chemical/Platelet Aggregation Inhibitors, http://linkedlifedata.com/resource/pubmed/chemical/Platelet Glycoprotein GPIIb-IIIa..., http://linkedlifedata.com/resource/pubmed/chemical/SC 54701A, http://linkedlifedata.com/resource/pubmed/chemical/Tyrosine, http://linkedlifedata.com/resource/pubmed/chemical/Valerates, http://linkedlifedata.com/resource/pubmed/chemical/lamifiban, http://linkedlifedata.com/resource/pubmed/chemical/tirofiban
pubmed:status
MEDLINE
pubmed:month
Nov
pubmed:issn
0006-4971
pubmed:author
pubmed:issnType
Print
pubmed:day
15
pubmed:volume
92
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
3675-83
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
1998
pubmed:articleTitle
Association between ligand-induced conformational changes of integrin IIbbeta3 and IIbbeta3-mediated intracellular Ca2+ signaling.
pubmed:affiliation
The Second Department of Internal Medicine, Osaka University Medical School, Osaka, Japan; the New Drug Research Laboratory, Fujisawa Pharmaceutical Co, Ltd, Osaka, Japan.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't