Dynamic control of the dopamine transporter in neurotransmission and homeostasis

摘要

RIT2-DAT association acts as DAT endocytic brake. PKC activation promotes the dissociation of RIT2 from DAT, enhances DAT ubiquitination by Nedd2-4, and targets DAT to clathrin-mediated endocytosis. Ubiquitinated DAT is recruited to ESCRT-Hrs complex which sorts DAT for lysosomal degradation. Conversely, DAT substrate activates intracellular effector TAAR1 and RhoA GTPase, which orchestrates actin polymerization through Arp2/3 near the plasma membrane and mediates clathrin-independent endocytosis. Substrate induced DAT internalization preferentially targets DAT to Rab11 mediated plasma membrane recycling, possibly through retromer-WASH (the endosomal cargo retrieval complex). This figure is created with BioRender.com.