12  Both the Oat and Oatp transporters appear to be exchangers. Using Xenopus oocytes transfected with Oat3, influx of labelled p-aminohippuric acid (PAH) or estrone sulphate was found to be coupled in some way to movement of glutarate, and probably other dicarboxylates, in the opposite direction, i.e. there was trans-stimulation of transport [620]. Interestingly however, influx of labelled estrone sulphate, was not stimulated by increased internal concentration of estrone sulphate, or PAH, i.e. there was no "self" trans-stimulation [236]. For Oatp transporters the exchange has different properties. For instance for Oatp1a4 (Oatp2) expressed in Xenopus oocytes suspended in low bicarbonate solution, increased concentrations of a variety of solutes present inside the cells, including taurocholate, glutathione, and glutathione conjugates, stimulate influx of labelled taurocholate [621]. However, when Oatp1a4 is expressed in a HeLa cell line suspended in bicarbonate buffered solution, the influx of taurocholate seems to be coupled to efflux of bicarbonate [622]. This coupling with bicarbonate has been confirmed using a number of different Oatp transporters expressed in CHO cells [623].
Exchangers are able to perform secondary active transport by coupling the downhill transport of one solute to the uphill movement of the other. Thus the demonstration of uphill transport from brain to blood might correspond to abluminal secondary active transport into the endothelial cells driven by an outward gradient of something like glutarate or glutathione or to luminal primary active transport out of the endothelial cells via an ABC transporter or to both. For instance PAH may be taken up into the cells by secondary active transport via Oat3 and subsequently expelled from them by primary active transport via an ABC transporter, possibly MRP4 [560]. Further work is required to establish the interplay of the effects of the various transporters.