Localization of S1P₁Receptor Signaling in the rat, mouse and human Central Nervous System

Abstract

Some specific lipid molecules present in the brain are signaling molecules at the intracellular compartments or behaving as neurotransmitters or neuromodulators of other systems, binding to specific G protein-coupled receptors (GPCR) for neurolipids. One of these receptors is the sphingosine 1-phosphate receptor subtype 1, coupled to Gi/o-proteins and involved in cell proliferation, growth or neuroprotection. Thus, an interesting target for neurodegenerative diseases, such as Alzheimers. The present study compares the human cerebral distribution of the activity mediated by S1P1 receptor with the that in the brain of rodent experimental models, rat and mice by functional autoradiography, measuring the [35S]GTPyS binding stimulated by the S1P1 receptor selective agonist CYM-5442 to get the anatomy of the S1P1 receptor activity. The S1P1 receptor-mediated activity is, together with that of the CB1 cannabinoid receptor, one of the highest recorded for any GPCR in most of the grey matter areas of the brain, reaching up to 50%-500% over basal, depending on the agonist and brain area. The S1P1 receptor signaling is very relevant in those areas that regulate learning and memory processes, such as the basal forebrain, but also in others involved in control of motor processes or nociception e.g. basal ganglia. The results also reveal that the rat would be a preferable experimental model to extrapolate for the S1P1 receptor-mediated responses in human brain.