Mechanisms of dopamine transporter regulation in normal and disease states

Abstract

The dopamine transporter (DAT) controls the spatial and temporal dynamics of dopamine (DA) neurotransmission by driving reuptake of extracellular transmitter into presynaptic neurons. Many diseases such as depression, bipolar disorder, Parkinson’s disease, and attention deficit hyperactivity disorder are associated with abnormal DA levels, implicating DAT as a factor in their etiology. Medications used to treat these disorders and many addictive drugs target DAT and enhance dopaminergic signaling by suppressing transmitter reuptake. We now understand that transport and binding properties of DAT are regulated by complex and overlapping mechanisms that provide neurons the ability to modulate DA clearance in response to physiological demands. These processes are controlled by endogenous signaling pathways and affected by exogenous transporter ligands, demonstrating their importance for normal neurotransmission, drug abuse, and disease treatments. Increasing evidence supports the disruption of these mechanisms in DA disorders, implicating dysregulation of transport in disease etiologies and suggesting these processes as potential points for therapeutic manipulation of DA availability.

Kinase-dependent Regulation of Monoamine Neurotransmitter Transporters

“…Over the past two decades, it has become amply clear that MA transporters are posttranslationally modified by phosphorylation under basal conditions and in response to activation of multiple signaling pathways (Vrindavanam et al, 1996;Huff et al, 1997;Vaughan et al, 1997;Ramamoorthy et al, 1998;Ramamoorthy et al, 2011;Vaughan and Foster, 2013). Figures 1-3 show serine, threonine, and tyrosine residues on DAT, NET, and SERT that can act as potential phosphorylation sites that could be targeted by kinases in these signaling pathways.…”

Regulation of the Dopamine and Vesicular Monoamine Transporters: Pharmacological Targets and Implications for Disease

“…Given the vast scope of the field, only selected mechanisms and disorders are discussed herein. These are not all encompassing, and the reader is referred to additional recent reviews (Sulzer et al, 2005;Alter et al, 2013;Schmitt et al, 2013;Vaughan and Foster, 2013;Howell and Negus, 2014;Nickell et al, 2014).…”

The rare DAT coding variant Val559 perturbs DA neuron function, changes behavior, and alters in vivo responses to psychostimulants

“…The presynaptic DA transporter (DAT) is the primary mechanism for terminating DA signaling at the synapse (9) and is the primary target for several psychostimulant drugs including cocaine (COC), methylphenidate (MPH), and amphetamine (AMPH). COC and MPH are DAT antagonists, elevating extracellular DA levels by preventing DAT-mediated DA reuptake (10). AMPH actions are more complex (11).…”