Our results, showing that GluN2B subunits are internalized through an endocytic process triggered by S1P signalling mainly via activation of S1P1 and S1P4 and, to a minor extent, S1P3 and S1P5, reinforce the great protective value of S1P against the abnormal activation of extrasynaptic NMDARs in the cytotoxic cascade responsible for neurodegeneration in AD. The gene discussed is S1PR3; the disease is Alzheimer disease.