Expression, localization, and function of MRP5 (ABCC5), a transporter for cyclic nucleotides, in human placenta and cultured human trophoblasts: effects of gestational age and cellular differentiation.

The placenta functions both as site for nutrition and protection of the fetus. Transport proteins, including members of the multidrug resistance protein (MRP)/ABCC subfamily, have been recognized to contribute to the latter function. MRP5 (ABCC5) was identified as transmembrane transport protein for cyclic nucleotides, especially 3',5'-cyclic GMP (cGMP), indicating an additional role in signal transduction and a potential role in placenta development. We therefore studied expression, localization, and function of MRP5 in placenta of different gestational ages. Quantitative real-time polymerase chain reaction revealed expression of MRP5 in all 60 samples from pre-term and term placenta, with a decreasing mean expression with gestational age (MRP5/18S-ratio x 1000; < 32 weeks: 2.91 +/- 0.73, n = 15; 32 to 37 weeks: 2.10 +/- 0.87, n = 15; > 37 weeks: 0.46 +/- 0.08, n = 30; P < 0.01). Immunofluorescence microscopy with an anti-MRP5 antibody indicated localization of MRP5 preferentially in the basal membrane of syncytiotrophoblasts and in and around fetal vessels. ATP-dependent [(3)H]cGMP transport as evidence for MRP5 function could be demonstrated in isolated basal membrane vesicles. Moreover, the influence of cellular differentiation on MRP5 expression was studied in isolated trophoblasts, revealing an increase of the MRP5 expression in parallel with the hCG production (MRP5/18S-ratio x 1000 was 2.4 +/- 0.5 at day 5 of culture and 1.45 +/- 0.5 at day 0 of culture, n = 3 preparations, significant difference with P < 0.05). In conclusion, MRP5 expression depends on gestational age and varies throughout the differentiation process. In view of the important role of cGMP for cellular differentiation, MRP5 may play a role in placental development in context with a specific need for cellular cGMP export.