Modulation of prostaglandin transport activity of SLCO2A1 by annexin A2 and S100A10.

Solute carrier organic anion transporter family member 2A1 (SLCO2A1) is a prostaglandin (PG) transporter and serves as the osmosensitive ATP-permeable maxi-anion channel (Maxi-Cl). Since a heterotetrameric complex of annexin A2 (ANXA2) and S100A10 is obligatory for the channel activity, the present study aimed to determine if they regulate SLCO2A1-mediated PG transport. This study examined PGE uptake and ATP release in and/or knockout (KO) murine breast C127 cells. Deletion of decreased PGE-d4 uptake by wild-type (WT) cells in an isotonic medium (290 mosmol/kgHO). Decreased osmolarity (135 mosmol/kgHO) stimulated ATP release but did not affect PGE uptake kinetics, showing (1,280 nM) and (10.38 pmol/15 s/mg protein) similar to those in isotonic medium (1,227 nM and 10.65 pmol/15 s/mg protein), respectively, in WT cells. Deletion of associated with loss of diminished SLCO2A1-mediated ATP release and uncompetitively inhibited PGE uptake with lowered (376 nM) and (2.59 pmol/15 s/mg protein). Moreover, the immunoprecipitation assay confirmed the physical interaction of ANXA2 with SLCO2A1 in WT cells. Enforcement of ANXA2 expression to KO cells partially restored PGE uptake and increased (744.3 nM) and (9.07 pmol/15 s/mg protein), whereas the uptake clearance (/) did not change much regardless of ANXA2 expression. These results suggest that an ANXA2/S100A10 complex modulates PG transport activity but osmolality has little effect on it; therefore, the bound form of SLCO2A1, which functions as a PG transporter and Maxi-Cl, may exist regardless of changes in the cell volume. A previous study indicated that the ANXA2/S100A10 complex represents the regulatory component of SLCO2A1-mediated Maxi-Cl channel activity. The present study showed that apparent PGE uptake by C127 cells was osmoinsensitive and uncompetitively inhibited by loss of ANXA2 expression, demonstrating that ANXA2 is a regulatory factor of SLCO2A1-mediated PG transport activity.