Dynamic control of the dopamine transporter in neurotransmission and homeostasis

Abstract

The dopamine transporter (DAT) transports extracellular dopamine into the intracellular space contributing to the regulation of dopamine neurotransmission. A reduction of DAT density is implicated in Parkinson's disease (PD) by neuroimaging; dopamine turnover is dopamine turnover is elevated in early symptomatic PD and in presymptomatic individuals with monogenic mutations causal for parkinsonism. As an integral plasma membrane protein, DAT surface expression is dynamically regulated through endocytic trafficking, enabling flexible control of dopamine signaling in time and space, which in turn critically modulates movement, motivation and learning behavior. Yet the cellular machinery and functional implications of DAT trafficking remain enigmatic. In this review we summarize mechanisms governing DAT trafficking under normal physiological conditions and discuss how PD-linked mutations may disturb DAT homeostasis. We highlight the complexity of DAT trafficking and reveal DAT dysregulation as a common theme in genetic models of parkinsonism.

Fig. 1. Dopamine transporter surface expression is regulated through endocytic trafficking.

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.

Fig. 2. A model for the physiological and pathological roles of PD-lined genes in DAT regulation.

Dopamine transporter trafficking is regulated by various mechanisms, many of which overlap with key molecular mechanisms compromised by PD-linked mutations. α-synuclein and Rit2 interact with DAT and regulate both surface expression and dopamine uptake kinetics. LRRK2 may regulate DAT trafficking either through axonal transport and/or endocytic trafficking. Parkin is proposed to ubiquitinate improperly folded DAT and increase its turnover rate. VPS35 is responsible for recruiting internalized DAT to a recycling fate. This figure is created with BioRender.com.