CLONING, PHARMACOLOGICAL CHARACTERIZATION, AND GENOMIC LOCALIZATION OF THE HUMAN CREATINE TRANSPORTER

The complete coding sequence from a human creatine transporter cDNA wa s isolated from a kidney library. This transporter is a member of a su perfamily of proteins which includes the family of Na+- and Cl--depend ent transporters responsible for the uptake of certain neurotransmitte rs (e.g. dopamine, GABA, serotonin, and norepinephrine), and amino aci ds (e.g. glycine). Within this family, the human creatine transporter is strongly related to a subfamily of sequences which includes the tra nsporters for taurine, GABA, and betaine, and this cDNA is approximate ly 98% amino acid identical to sequences that have been reported from rat and rabbit as choline and creatine transporters respectively. Phar macological characterization demonstrated that the protein product of this cDNA mediated high affinity (K(m) = 77 +/- 6 muM) creatine uptake , which was blocked by creatine analogs with high affinity. There was no specific transport of choline. Northern analysis demonstrated highe st levels of mRNA expression in human skeletal muscle, kidney, and hea rt, with lower levels in brain and other tissues. Expression within th e kidney was evenly distributed between cortex and medulla. Genetic ma pping in the mouse localizes the creatine transporter to a region on t he X chromosome in linkage conservation with the human region Xq28, th e location of the genes for several neuromuscular diseases.