Stimulation of the creatine transporter SLC6A8 by the protein kinases SGK1 and SGK3

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 S422DSGK1, but not inactive K127NSGK1. Kinetic analysis revealed that S422DSGK1 enhanced maximal current without significantly altering affinity. The effect of SGK1 was mimicked by the constitutively active isoform S419DSGK3 but not by inactive K119NSGK3, wild type isoform SGK2 or constitutively active related kinase T308D,S473DPKB. 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.