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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
7
|
| pubmed:dateCreated |
1996-11-7
|
| pubmed:abstractText |
In the present study, we have investigated the mechanism of affinity modulation of alpha IIb beta 3 by chymotrypsin. We first confirmed that alpha-chymotrypsin could activate alpha IIb beta 3 (approximately 7,000 molecules per platelet) without major intracellular signaling. However, we unexpectedly found that high concentrations of amiloride dose-dependently inhibited 125I-fibrinogen binding to the chymotrypsin-treated platelets, as well as the platelet aggregation (IC50 [50% inhibitory concentration] for fibrinogen binding, 530 mumol/L). In contrast, amiloride did not inhibit alpha IIb beta 3 activation induced by anti-alpha IIb beta 3 monoclonal antibody PT25-2 or AP5. To identify the pathway involved, the effects of alteration of Na+ gradient in platelets were examined. Lowering Na+ gradient by replacing extracellular Na+ with tetramethylammonium (TMA) increased the number of activated alpha IIb beta 3 by twofold, as assessed by fibrinogen-binding assay. The incubation of platelets with ouabain, a Na+/K(+)-adenosine triphosphatase (ATPase) inhibitor, further augmented alpha IIb beta 3 activation. These data suggested that a likely candidate for the pathway was Na+/Ca2+ exchanger. At 140 mmol/L [Na+]o, 45Ca2+ influx to the chymotrypsin-treated platelets was twofold greater than that to non-treated platelets. Replacement of Na+ with TMA further increased the Ca2+ influx, and the increase was inhibited by amiloride dose-dependently. 3',4'-Dichlorobenzamil (DCB) and bepridil, relatively specific inhibitors of Na+/Ca2+ exchanger, also inhibited the chymotrypsin-induced alpha IIb beta 3 activation, and the IC50 values of these inhibitors for fibrinogen binding were 25 mumol/L and 52 mumol/L, respectively. Moreover, platelet aggregation induced by various physiologic agonists was inhibited by DCB or bepridil, while platelet agglutination by ristocetin was not. Our data newly suggest that Na+/Ca2+ exchanger operating in reverse mode may be directly involved in inside-out signaling that activates alpha IIb beta 3.
|
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
AIM
|
| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/3',4'-dichlorobenzamil,
http://linkedlifedata.com/resource/pubmed/chemical/Amiloride,
http://linkedlifedata.com/resource/pubmed/chemical/Antibodies, Monoclonal,
http://linkedlifedata.com/resource/pubmed/chemical/Bepridil,
http://linkedlifedata.com/resource/pubmed/chemical/Calcium,
http://linkedlifedata.com/resource/pubmed/chemical/Carrier Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Chymotrypsin,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Fibrinogen,
http://linkedlifedata.com/resource/pubmed/chemical/Ouabain,
http://linkedlifedata.com/resource/pubmed/chemical/Platelet Glycoprotein GPIIb-IIIa...,
http://linkedlifedata.com/resource/pubmed/chemical/Quaternary Ammonium Compounds,
http://linkedlifedata.com/resource/pubmed/chemical/Sodium,
http://linkedlifedata.com/resource/pubmed/chemical/Sodium-Calcium Exchanger,
http://linkedlifedata.com/resource/pubmed/chemical/Sodium-Potassium-Exchanging ATPase,
http://linkedlifedata.com/resource/pubmed/chemical/tetramethylammonium
|
| pubmed:status |
MEDLINE
|
| pubmed:month |
Oct
|
| pubmed:issn |
0006-4971
|
| pubmed:author | |
| pubmed:issnType |
Print
|
| pubmed:day |
1
|
| pubmed:volume |
88
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
2594-602
|
| pubmed:dateRevised |
2007-11-15
|
| pubmed:meshHeading |
pubmed-meshheading:8839852-Amiloride,
pubmed-meshheading:8839852-Antibodies, Monoclonal,
pubmed-meshheading:8839852-Bepridil,
pubmed-meshheading:8839852-Biological Transport, Active,
pubmed-meshheading:8839852-Calcium,
pubmed-meshheading:8839852-Carrier Proteins,
pubmed-meshheading:8839852-Chymotrypsin,
pubmed-meshheading:8839852-Enzyme Inhibitors,
pubmed-meshheading:8839852-Fibrinogen,
pubmed-meshheading:8839852-Humans,
pubmed-meshheading:8839852-Ouabain,
pubmed-meshheading:8839852-Platelet Aggregation,
pubmed-meshheading:8839852-Platelet Glycoprotein GPIIb-IIIa Complex,
pubmed-meshheading:8839852-Protein Binding,
pubmed-meshheading:8839852-Quaternary Ammonium Compounds,
pubmed-meshheading:8839852-Sodium,
pubmed-meshheading:8839852-Sodium-Calcium Exchanger,
pubmed-meshheading:8839852-Sodium-Potassium-Exchanging ATPase
|
| pubmed:year |
1996
|
| pubmed:articleTitle |
Affinity modulation of the platelet integrin alpha IIb beta 3 by alpha-chymotrypsin: a possible role for Na+/Ca2+ exchanger.
|
| pubmed:affiliation |
Second Department of Internal Medicine, Osaka University Medical School, Japan.
|
| pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
|