Functional characterization of monocarboxylate transporter 12 (SLC16A12/MCT12) as a facilitative creatine transporter.

SLC16A12/MCT12 has been recently identified as a creatine transporter in a Xenopus oocyte expression system; however, the mechanism, by which MCT12 transports creatine, remains unclear. This study was performed to determine the functional and molecular characteristics of MCT12 in mammalian cells. The results showed that the uptake of [14C]creatine was not significantly increased in HEK293 cells transiently expressing MCT12 with or without CD147, a molecular chaperone, compared with mock cells. When [14C]creatine was accumulated in the cells with the aid of SLC6A8/CRT1, a concentrative creatine transporter, followed by assessing the remaining intracellular [14C]creatine after initiating efflux, coexpression of MCT12 resulted in a decrease in the intracellular [14C]creatine and remarkably enhanced the efflux of [14C]creatine from the cells in a time-dependent manner. This activity was not affected by extracellular pH. The creatine efflux activity involved dissipation by the mutations of conserved charged amino acids such as Arg37, Asp65 and Asp299 in the transmembrane domains, indicating direct involvement of MCT12 in the creatine efflux. These results suggest that MCT12 mediates facilitative diffusion of creatine, depending on the concentration gradient across the plasma membrane in mammalian cells. The finding may provide important clues to understanding the disposition kinetics of creatine and its derivatives.