Creatine and creatine phosphate are essential for the maintenance of ATP levels in tissues with high and fluctuating energy demands such as skeletal muscle and brain. Creatine kinase catalyzes the reversible transfer of a phosphate from creatine phosphate to ADP regenerating ATP. In mammals, creatine is either synthesized by sequential reactions occurring in the kidney and liver or obtained from the diet. Muscle cells do not synthesize creatine. They take it up via a special sodium-dependent transporter, the creatine transporter (CRT). Inhibition of creatine transport in experimental animals causes muscle weakness. A specific uptake system for creatine has been demonstrated in skeletal muscle, human monocytes, macrophages and astroglial-rich cultures. CRT exhibits significant homology to the Na+ and Cl- -dependent GABA/norepinephrine (GAT-1/norepinephrine transporter) gene family of neurotransmitter transporters. All members of this family are predicted to contain 12-membrane-spanning domains, to contain a large extracellular loop containing sites for N-linked glycosylation between the third and fourth transmembrane domains, and to have the amino and carboxyl termini facing the cytoplasmic side of the membrane. At least two CRT have been cloned, expressed and characterized. CRT1 or CT1 (mouse, human 635aa, chromosome X28) is expressed in kidney, muscle, brain and other tissues. CT2 (human 426aa, chromosome 16p11.2) is testis specific.