Department of Physiology and Pharmacology, University of Bristol, Bristol, UK.
J Thromb Haemost. 2010 Mar;8(3):454-62. doi: 10.1111/j.1538-7836.2009.03722.x. Epub 2009 Dec 11.
Platelet activation is a complex balance of positive and negative signaling pathways. The protein kinase C (PKC) family is a major regulator of platelet granule secretion, integrin activation, aggregation, spreading and procoagulant activity. As broad-spectrum PKC inhibitors reduce secretion and aggregation, the PKC family is generally considered to be a positive regulator of platelet activation. However, the individual members of the PKC family that are expressed in platelets are regulated in different ways, and an increasing body of evidence indicates that they have distinct, and often opposing, roles. Many of the recent advances in understanding the contributions of individual PKC isoforms have come from mouse gene knockout studies. PKCalpha, a classic isoform, is an essential positive regulator of granule secretion and thrombus formation, both in vitro and in vivo. Mice lacking PKCalpha show much reduced thrombus formation in vivo but do not have a bleeding defect, suggesting that PKCalpha could be an attractive antithrombotic target. Important, apparently non-redundant, roles, both positive and negative, for the novel PKC isoforms delta, theta and epsilon in granule secretion have also been proposed, indicating highly complex regulation of this essential process. Similarly, PKCbeta, PKCdelta and PKCtheta have non-redundant roles in platelet spreading, as absence of either PKCbeta or PKCtheta reduces spreading, whereas PKCdelta negatively regulates filopodial formation. This negative signaling by PKCdelta may reduce platelet aggregation and so restrict thrombus formation. In this review, we discuss the current understanding of the regulation and functions of individual PKC isoforms in platelet activation and thrombus formation.
血小板激活是一个复杂的正、负信号通路平衡的过程。蛋白激酶 C（PKC）家族是血小板颗粒分泌、整合素激活、聚集、扩展和促凝血活性的主要调节剂。由于广谱 PKC 抑制剂可减少分泌和聚集，因此 PKC 家族通常被认为是血小板激活的正向调节剂。然而，在血小板中表达的 PKC 家族的各个成员受到不同的调节，越来越多的证据表明它们具有不同的、通常是相反的作用。对个体 PKC 同工型作用的理解的许多最新进展来自于小鼠基因敲除研究。经典同工型 PKCalpha 是体外和体内颗粒分泌和血栓形成的必需正向调节剂。缺乏 PKCalpha 的小鼠体内血栓形成明显减少，但没有出血缺陷，表明 PKCalpha 可能是一种有吸引力的抗血栓靶点。同样，新型 PKC 同工型 delta、theta 和 epsilon 在颗粒分泌中也提出了重要的、显然非冗余的正向和负向作用，表明对这一基本过程的高度复杂调节。同样，PKCβ、PKCδ 和 PKCθ 在血小板扩展中具有非冗余的作用，因为缺乏 PKCβ 或 PKCθ 会减少扩展，而 PKCδ 则负调节丝状伪足的形成。PKCδ 的这种负信号可能会减少血小板聚集，从而限制血栓形成。在这篇综述中，我们讨论了目前对个体 PKC 同工型在血小板激活和血栓形成中的调节和功能的理解。
