FIGURE 2. Schematic representation of the different compartments involved in the regulation and function of S1P in vivo.

At the intracellular compartment, S1P is formed after stimulation by different agonists, and it signals as an intracellular mediator. Other enzymes involved in the metabolism of sphingolipids (see Figure 1) can alter its levels and the levels of other metabolites to shape the cellular response. At the membrane compartment, S1P can exit the cell via plasma membrane transporters and engage autocrine (via binding to S1P receptors in the same cell type) or paracrine loops (via binding to S1P receptors in other cell types). At the extracellular compartment, local tissue S1P levels, circulating S1P or blood-tissue gradients may affect the expression of S1P receptors in different cells and their function in proximal or distant cells. The S1P present in the extracellular environment originates from the export of intracellularly generated S1P. Alternatively, secreted sphingolipid enzymes (see Figure 1) or, potentially, autotaxin can generate S1P extracellularly. Various stimuli or changes in physiological conditions can indirectly change S1P levels in the extracellular environment (i.e regulation of S1P lyase or S1P phosphatases (SPP), activation of platelets or mast cells, etc), affecting other cells responses. Reciprocally, activation of S1PR may alter the composition of external stimuli in the physiological environment.