Activation of platelet gpIIbIIIa by phospholipase C from Clostridium perfringens involves store-operated calcium entry.
Clostridium perfringens gas gangrene is characterized by rapid tissue destruction, and amputation remains the single best treatment. Previous studies have demonstrated that tissue destruction follows C. perfringens phospholipase C (PLC)-induced, platelet gpIIbIIIa-mediated formation of occlusive intravascular platelet/leukocyte aggregates. In this study, the intracellular signaling events leading to activation of gpIIbIIIa by PLC were investigated. PLC activated surface expressed gpIIbIIIa and mobilized gpIIbIIIa from internal stores. Chelation of intracellular calcium or inhibition of store-operated calcium entry each blocked PLC-induced activation of gpIIbIIIa, whereas inhibition of protein kinase C was without effect. Thus, PLC initiates an "inside-out" signaling cascade that begins with depletion of internal calcium stores, is sustained by an influx of calcium through store-sensitive channels, and culminates in the functional activation of gpIIbIIIa. These findings suggest that calcium-channel blockade and strategies targeting gpIIbIIIa may prevent vascular occlusion, maintain tissue viability, and provide an alternative to radical amputation for patients with gas gangrene.
Bryant
Amy E
AE
Infectious Diseases Section, Veterans Affairs Medical Center, Boise, Idaho 83702, USA. abryant@mindspring.com
Bayer
Clifford R
CR
Hayes-Schroer
Susan M
SM
Stevens
Dennis L
DL
D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects*; D003016:Clostridium perfringens / Q000201:enzymology*; D004305:Dose-Response Relationship, Drug; D054641:Dual Specificity Phosphatase 2; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000235:genetics / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D054648:Protein Phosphatase 2; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D013997:Time Factors; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology
D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011493:Protein Kinase C; D054648:Protein Phosphatase 2; C517032:DUSP2 protein, human; D054641:Dual Specificity Phosphatase 2; D017027:Protein Tyrosine Phosphatases; D010738:Type C Phospholipases; D002118:Calcium