Activation of Glycoprotein VI (GPVI) and C-type Lectin-like receptor-2 (CLEC-2) underlies platelet activation by diesel exhaust particles and other charged/hydrophobic ligands

Platelets are activated by a range of stimuli that share little or no resemblance in structure to each other or to recognised ligands, including diesel exhaust particles (DEP), small peptides (4N1-1, Champs, LSARLAF), proteins (histones), and large polysaccharides (fucoidan, dextran sulphate). This miscellaneous group stimulate aggregation of human and mouse platelets through the GPVI-FcR-γ-chain complex and/or CLEC-2 as shown using platelets from mice deficient in either or both of these receptors. In addition, all of these ligands stimulate tyrosine phosphorylation in GPVI/CLEC-2 double-deficient platelets, indicating that they bind to additional surface receptors, although only in the case of dextran sulphate does this lead to activation. DEP, fucoidan and dextran sulphate, although not the other agonists, activate GPVI and CLEC-2 in transfected cell lines as shown using a sensitive reporter assay confirming a direct interaction with the two receptors. We conclude that this miscellaneous group of ligands bind to multiple proteins on the cell surface including GPVI and/or CLEC-2, inducing activation. These results have pathophysiological significance in a variety of conditions that involve exposure to activating charged/hydrophobic agents.

Source: BJ Signal - April 7, 2015 Category: Biochemistry Authors: O M Alshehri, S Montague, S Watson, P Carter, N Sarker, B K Manne, J L. C. Miller, A B Herr, A Y Pollitt, C A O'Callaghan, S P Kunapuli, M Arman, C E Hughes, S P Watson Tags: BJ Signal Source Type: research