The N terminus of the protein folds as a helical cap above the top of the receptor and therefore it limits the access of the ligands to the amphipathic binding pocket.

In addition, helices ECL1 and ECL2 pack tightly against the N-terminal helix, further occluding the access of the ligand from the extracellular space.

S1P or S1P analogs are likely to reach the binding pocket from within the cell membrane and not from the extracellular space, may be through an opening between helices I and VII.

[11] Like the other members of the GPCR family, S1PR1 senses its ligand from outside the cell and activates intracellular signal pathways that at last lead to cellular responses.

S1PR1 is responsive to the S1P gradient between the lymphoid tissues (low S1P) and the lymph (high S1P), facilitating T cell movement through the endothelial barrier.

[14] However, upon T cell activation in lymphoid organs via cytokine and T-cell receptor signaling, the protein Cluster of Differentiation 69 (CD69) is expressed and forms a complex with S1PR1.

This interaction, involving CD69 transmembrane domain and the helix-4 of S1PR1, leads to S1PR1 internalization and degradation, preventing S1P binding and downstream signaling.

[19] Moreover, the binding of S1P to S1PR1 is implicated in the formation of cell-cell adherens junctions, therefore inhibiting paracellular permeability of solutes and macromolecules.

Fingolimod, a drug which internalizes the receptor, is approved as a disease modifying agent in Multiple sclerosis.