Department of Pharmacology, Research Center of Pharmacology and Experimental Therapeutics, Institut für Pharmakologie, Ernst-Moritz-Arndt-University, Friedrich-Loeffler-Str. 23d, D-17487, Greifswald, Germany.
Am J Pathol. 2010 Mar;176(3):1097-103. doi: 10.2353/ajpath.2010.090425. Epub 2010 Feb 4.
We previously showed that the MRP4 (ABCC4) transporter is expressed in human platelet delta-granules and may be involved in ADP transport. We now demonstrate by immunoblotting and immunofluorescence microscopy that platelet MRP4 is absent in two patients with a platelet delta-storage pool deficiency (delta-SPD)-like phenotype with reduced platelet adenine nucleotide (AN) but normal serotonin levels, whereas their other membrane marker proteins of platelet granules were normally expressed and localized. In these patients, MRP4 was present in lymphocytes, and the coding region of their MRP4/ABCC4 gene did not show any mutation that explained the lack of expression. In platelets with "classic" delta-SPD (low AN and serotonin levels), MRP4 was quantitatively (immunoblot) normal, but, like other delta-granules membrane marker proteins (eg, LAMP2), was mostly displaced from delta-granules to patches at the plasma membrane, suggesting that platelets with classic delta-SPD have an abnormality that impairs the assembly of normal delta-granules. Thus, defective expression of platelet MRP4 is associated with selective defect in AN storage. The genetic basis of the new delta-SPD phenotype remains to be elucidated.
我们之前已经证实，多药耐药相关蛋白 4（MRP4，即 ABCC4）转运体在人血小板δ-颗粒中表达，并可能参与 ADP 的转运。我们现在通过免疫印迹和免疫荧光显微镜发现，在两名具有类似血小板δ-储存池缺陷（δ-SPD）表型的患者中，血小板 MRP4 缺失，其血小板腺嘌呤核苷酸（AN）减少，但 5-羟色胺水平正常，而其其他膜颗粒标记蛋白正常表达和定位。在这些患者中，MRP4 存在于淋巴细胞中，且其 MRP4/ABCC4 基因的编码区没有任何突变可解释其表达缺失。在“经典”δ-SPD（低 AN 和 5-羟色胺水平）的血小板中，MRP4 的定量（免疫印迹）正常，但与其他 δ-颗粒膜标记蛋白（如 LAMP2）一样，其大多从 δ-颗粒移位到质膜斑，表明具有经典 δ-SPD 的血小板存在一种异常，损害了正常 δ-颗粒的组装。因此，血小板 MRP4 的表达缺陷与 AN 储存的选择性缺陷有关。新型 δ-SPD 表型的遗传基础仍有待阐明。
