A Defect in Collagen Receptor-Ca2+ Signaling System in Platelets from Cattle with Chediak-Higashi Syndrome

Abstract

SummaryDecreased platelet aggregation to collagen is a cause for bleeding diathesis of Chediak-Higashi syndrome (CHS). We investigated whether the collagen receptor-Ca2+ signaling system was impaired in platelets from cattle affected with CHS. A collagen-induced increase in cytosolic Ca2+ ([Ca2+]i) was depressed in CHS platelets, which was accompanied by a decrease in the production of inositol 1,4,5-trisphosphate. When the influences of endogenous arachidonic acid metabolites and ADP were excluded, convulxin or collagen-related peptide, which are specific agonists for the collagen receptor GPVI, increased [Ca2+]i in both normal and CHS platelets. In contrast, rhodocytin, which was thought to activate another collagen receptor GPIa/IIa, increased [Ca2+]i in CHS platelets to a lesser extent than in normal ones. Cytochalasin D, an actin polymerization inhibitor, depressed the response to collagen or rhodocytin but not the response to convulxin. Adhesion of CHS platelets to acid soluble type I collagen, which was mediated by GPIa/IIa, was similar to that of normal platelets. These results suggest that a defect in the rhodocytin-sensitive pathway is responsible for decreasing the response to collagen in CHS platelets. It remains to be determined which receptor is associated with the mechanism.

Platelet Dysfunction in Chediak-Higashi Syndrome-Affected Cattle.

“…Unlike human platelets, however, arachidonic acid metabolites seem to play a negligible role in bovine platelets, because cyclooxygenase inhibitors showed no effect on aggregation response to collagen, ADP or platelet-activating factor in platelets from healthy cattle [11,17,24]. Consistent with these reports, our study ] i response to collagen in bovine CHS platelets was slightly decreased by pretreatment with cyclooxygenase inhibitors, whereas it was not affected in normal platelets [59][60][61]. Probably, contribution of TXA 2 increased in the collagen-induced response of CHS platelets as a compensation for a decrease in release of ADP, although we do not know the mechanism for the compensation.…”

“…It has not been determined whether rhodocytin binds to GPIa/IIa in bovine platelets. If rhodocytin does not bind to GPIa/IIa, our study [61] suggests that another receptor, which is sensitive to rhodocytin, participates in the collagen-induced activation. This receptor probably delivers a signal for full activation of GPVI when collagen acts on platelets.…”

“…In CHS platelets, the maximum increase in [Ca 2+ ] i induced by collagen at each concentration was significantly lower than in normal platelets [59]. The fraction of collagen-induced Ca 2+ mobilization that was independent of endogenous agonists in CHS platelets was only about 15% of that in normal platelets [61] (Fig. 2A).…”

“…In fact, in vitro aggregation studies using platelets from CHS patients revealed that aggregation induced by collagen, which is an important platelet activator to form a thrombus when a vessel wall is injured, was remarkably impaired in platelets from almost all patients. In this review, we first describe abnormality in CHS platelets and possible causes for insufficient aggregation to collagen in CHS platelets.We have recently demonstrated that handling of cytosolic Ca 2+ due to a direct action of collagen was abnormal in platelets from Japanese Black cattle affected with CHS [59,61]. This observation suggests that a collagen receptor-Ca 2+ signaling system is impaired in CHS-affected platelets.…”

“…We have recently demonstrated that handling of cytosolic Ca 2+ due to a direct action of collagen was abnormal in platelets from Japanese Black cattle affected with CHS [59,61]. This observation suggests that a collagen receptor-Ca 2+ signaling system is impaired in CHS-affected platelets.…”