Glycogen synthase kinase-3ß supports serotonin transporter function and trafficking in a phosphorylation-dependent manner.

摘要: Serotonin (5-HT) transporter (SERT) plays a crucial role in serotonergic transmission the central nervous system, and any aberration causes serious mental illnesses. Nevertheless, cellular mechanisms that regulate SERT function trafficking are not entirely understood. Growing evidence suggests several protein kinases act as modulators. Here, we delineate molecular by which glycogen synthase kinase-3s (GSK3s) regulates SERT. When mouse striatal synaptosomes were treated with GSK3α/s inhibitor CHIR99021, observed significant increase function, Vmax , surface expression reduction 5-HT Km phosphorylation. To further study how molecule is affected GSK3α/s, used HEK-293 cells heterologous system. As synaptosomes, CHIR99021 treatment of expressing wild-type hSERT (hSERT-WT) resulted time dose-dependent elevation concomitant transporters because reduced internalization enhanced membrane insertion; silencing these siRNA also similarly hSERT. Converting putative phosphorylation site serine at position 48 to alanine (hSERT-S48A) completely abrogated effects both siRNA. Substantiating findings, over-expression constitutively active GSK3s hSERT-WT, but hSERT-S48A, density, Both hSERT-WT hSERT-S48A inhibited PKC activation or inhibition Akt, CaMKII, p38 MAPK, Src kinase. These findings provide new supports basal via serine-48