Creatine binds phosphate thus serving energy storage. Cellular creatine uptake is accomplished by the Na+,Cl-, creatine transporter CreaT (SLC6A8). The present study explored the regulation of SLC6A8 by the serum and glucocorticoid inducible kinase SGK1, a kinase upregulated during ischemia. In Xenopus oocytes expressing SLC6A8 but not in water injected oocytes creatine induced a current which was significantly enhanced by coexpression of wild type SGK1 and constitutively active (S422D)SGK1, but not inactive (K127N)SGK1. Kinetic analysis revealed that (S422D)SGK1 enhanced maximal current without significantly altering affinity. The effect of SGK1 was mimicked by the constitutively active isoform (S419D)SGK3 but not by inactive (K119N)SGK3, wild type isoform SGK2 or constitutively active related kinase (PKB)-P-T308D.S473D. In conclusion, the kinases SGK1 and SGK3 increase SLC6A8 activity by increasing the maximal transport rate of the carrier. Deranged SGK1 and/or SGK3 dependent regulation of SLC6A8 may affect energy storage particularly in skeletal muscle, heart, and neurons. (c) 2005 Elsevier Inc. All rights reserved.