Regulatory processes including receptor phosphorylation and intracellular trafficking, also referred to as receptor internalization, are important processes to terminate
G protein-coupled receptor (GPCR) signaling. Compelling evidence now indicates that internalization of a receptor is not necessarily the endpoint of signaling, but can also be the beginning of the activation of intracellular signaling pathways.
Sphingosine-1-phosphate (S1P) receptors, which are activated by the endogenous
phospholipid S1P, belong to the family of GPCRs. Interestingly, there is evidence indicating differential intracellular trafficking of one of the
S1P receptor subtypes, the
S1P1 receptor, upon agonist activation by either S1P or the synthetic agonist
FTY720-P. Moreover, the differential effect of
FTY720-P on
S1P1 receptor regulation has been suggested to be the mechanism of action of this
drug, which is now in Phase III clinical trials for the treatment of
multiple sclerosis. It is thus of importance to get a good insight into the regulation of S1P receptors. This review therefore gives a detailed overview about the current state of knowledge on
S1P receptor internalization and its functional implications, including some data on nuclear signaling of S1P receptors.