SPHK1 and nervous system disorder: Besides the S1P receptors, also the SphKs catalyzing S1P formation, SphK1 with cytoplasmic localization and SphK2, the predominant SphK isoform in the brain, with primarily nuclear localization (Igarashi et al., 2003) as well as the S1P degrading enzymes S1P lyase (S1PL; Le Stunff et al., 2002), S1P phosphatases (SPP1 and SPP2), and the lysophospholipid phosphatase 3 (LPP3; Brindley and Pilquil, 2009) have been found to be altered in several neurological diseases and also represent putative targets for drug development (Figure 1).