| First Author | Zheng Y | Year | 2015 |
| Journal | PLoS One | Volume | 10 |
| Issue | 3 | Pages | e0119739 |
| PubMed ID | 25793864 | Mgi Jnum | J:229625 |
| Mgi Id | MGI:5752698 | Doi | 10.1371/journal.pone.0119739 |
| Citation | Zheng Y, et al. (2015) Restoration of responsiveness of phospholipase Cgamma2-deficient platelets by enforced expression of phospholipase Cgamma1. PLoS One 10(3):e0119739 |
| abstractText | Receptor-mediated platelet activation requires phospholipase C (PLC) activity to elevate intracellular calcium and induce actin cytoskeleton reorganization. PLCs are classified into structurally distinct beta, gamma, delta, epsilon, zeta, and eta isoforms. There are two PLCgamma isoforms (PLCgamma1, PLCgamma2), which are critical for activation by tyrosine kinase-dependent receptors. Platelets express both PLCgamma1 and PLCgamma2. Although PLCgamma2 has been shown to play a dominant role in platelet activation, the extent to which PLCgamma1 contributes has not been evaluated. To ascertain the relative contributions of PLCgamma1 and PLCgamma2 to platelet activation, we generated conditionally PLCgamma1-deficient, wild-type (WT), PLCgamma2-deficient, and PLCgamma1/PLCgamma2 double-deficient mice and measured the ability of platelets to respond to different agonists. We found that PLCgamma2 deficiency abrogated alphaIIbbeta3-dependent platelet spreading, GPVI-dependent platelet aggregation, and thrombus formation on collagen-coated surfaces under shear conditions, which is dependent on both GPVI and alphaIIbbeta3. Addition of exogenous ADP overcame defective spreading of PLCgamma2-deficient platelets on immobilized fibrinogen, suggesting that PLCgamma2 is required for granule secretion in response to alphaIIbbeta3 ligation. Consistently, alphaIIbbeta3-mediated release of granule contents was impaired in the absence of PLCgamma2. In contrast, PLCgamma1-deficient platelets spread and released granule contents normally on fibrinogen, exhibited normal levels of GPVI-dependent aggregation, and formed thrombi normally on collagen-coated surfaces. Interestingly, enforced expression of PLCgamma1 fully restored GPVI-dependent aggregation and alphaIIbbeta3-dependent spreading of PLCgamma2-deficient platelets. We conclude that platelet activation through GPVI and alphaIIbbeta3 utilizes PLCgamma2 because PLCgamma1 levels are insufficient to support responsiveness, but that PLCgamma1 can restore responsiveness if expressed at levels normally achieved by PLCgamma2. |
