Sortilin/neurotensin receptor-3 and its derived peptides in depression

Sortilin, also called neurotensin (NTS) receptor-3 (NTSR3), displays a role of a multifunctional protein that is the consequence of its particular posttranslational and cellular properties. Sortilin is synthesized under a precursor form that is cleaved to generate a functional protein and a 44-amino acid peptide (named PE) at the level of late Golgi compartments. When present at the plasma membrane, sortilin is shedded by matrix metalloproteases leading to the release of a soluble form of the protein. Interestingly, in resting cells, sortilin is differentially distributed, 90% intracellularly and only 10% at the cell surface where the protein can play a role of receptor or coreceptor. Intracellular sortilin is involved in the sorting of other proteins to the plasma membrane and/or to the lysosomal pathway. Finally, the role of sortilin in depression comes from its interaction with the two-pore potassium channel TREK-1 that allows its sorting to the plasma membrane and also by the fact that PE and its shorter analog spadin are selective and specific blockers of this channel. The chapter summarizes the various roles of mature sortilin, soluble sortilin, and sortilin-derived peptides in the cellular and physiological mechanisms that are involved to detect or to treat depression.