Biomedical subjects

George L Dale

Publications and source records attributed to George L Dale.

3 recordsLinked to original sources

PubMed2003

COAT platelets.

PURPOSE OF REVIEW: COAT platelets are a recently described subpopulation of cells resulting from simultaneous activation with collagen and thrombin. The complete process by which COAT platelets are produced is still not clear, although significant recent progress has been made. RECENT FINDINGS: COAT platelets retain several procoagulant proteins on their surface by a previously unrecognized mechanism involving transglutaminase mediated conjugation of serotonin to released alpha-granule proteins. Fibrinogen and thrombospondin have been found to bind serotonin-conjugated proteins and thereby provide the requisite link for stabilization of serotonin-derivatized, procoagulant proteins on COAT platelets. SUMMARY: Multivalent interactions, resulting from traditional receptor interactions and binding of conjugated serotonin by fibrinogen and thrombospondin, result in exceptionally strong retention of procoagulant alpha-granule proteins on the surface of COAT platelets. The physiologic significance of this new subclass of platelets remains to be determined.

Blood Platelets↗

PubMed2002

Thrombospondin and fibrinogen bind serotonin-derivatized proteins on COAT-platelets.

Activation of platelets with 2 agonists, collagen and thrombin, reveals a subpopulation of cells referred to as COAT-platelets (collagen and thrombin activated). These cells are enriched in several membrane-bound, procoagulant proteins, including fibrinogen, thrombospondin, factor V, von Willebrand factor, and fibronectin. alpha-Granule proteins bound to COAT-platelets are derivatized with serotonin by a transglutaminase-mediated process, and the interaction of conjugated serotonins with unidentified serotonin binding sites on the platelet surface enhances retention of these proteins. We now demonstrate that both thrombospondin and fibrinogen provide the requisite serotonin binding sites. Thrombospondin and fibrinogen were identified using photoreactive cross-linking to an albumin-(serotonin)(6) conjugate during COAT-platelet production. We subsequently verified that biotin-albumin-(serotonin)(6) binds in vitro to thrombospondin, fibrinogen, and fibrinogen fragment D in a saturable manner. These data support a model for COAT-platelets where serotonin-derivatized procoagulant proteins interact with their respective receptors (eg, fibrinogen with glycoprotein IIb/IIIa or factor V with phosphatidylserine) as well as serotonin binding sites on fibrinogen and thrombospondin, resulting in a stable, multivalent complex on the cell surface.

Binding Sites↗

PubMed2002

Stimulated platelets use serotonin to enhance their retention of procoagulant proteins on the cell surface.

Activated platelets bind numerous adhesive and procoagulant proteins by receptor-mediated processes. Although there is little evidence to suggest that these processes are heterogeneous in platelets, we previously found that platelets co-stimulated with collagen and thrombin express functional alpha-granule factor V only on a subpopulation of cells. Here we show that these cells, referred to as 'COAT-platelets', bind additional alpha-granule proteins, including fibrinogen, von Willebrand factor, thrombospondin, fibronectin and alpha2-antiplasmin. These proteins are all transglutaminase substrates, and inhibitors of transglutaminase prevent the production of COAT-platelets. A synthetic transglutaminase substrate (CP15) also binds to COAT-platelets, and analysis by high performance liquid chromatography/mass spectrometry shows that a product is formed with a relative molecular mass (Mr) equal to CP15 plus 176. Serotonin, an abundant component of platelet-dense granules, has an Mr of 176, and fibrinogen isolated from COAT-platelets contains covalently linked serotonin. Synthetic bovine serum albumin-(serotonin)6 binds selectively to COAT-platelets and also inhibits the retention of procoagulant proteins on COAT-platelets. These data indicate that COAT-platelets use serotonin conjugation to augment the retention of procoagulant proteins on their cell surface through an as yet unidentified serotonin receptor.

Amino Acid Sequence↗