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

Abstract

Dopamine (DA) plays a well recognized role in a variety of physiologic functions such as movement, cognition, mood, and reward. Consequently, many human disorders are due, in part, to dysfunctional dopaminergic systems, including Parkinson's disease, attention deficit hyperactivity disorder, and substance abuse. Drugs that modify the DA system are clinically effective in treating symptoms of these diseases or are involved in their manifestation, implicating DA in their etiology. DA signaling and distribution are primarily modulated by the DA transporter (DAT) and by vesicular monoamine transporter (VMAT)-2, which transport DA into presynaptic terminals and synaptic vesicles, respectively. These transporters are regulated by complex processes such as phosphorylation, protein-protein interactions, and changes in intracellular localization. This review provides an overview of 1) the current understanding of DAT and VMAT2 neurobiology, including discussion of studies ranging from those conducted in vitro to those involving human subjects; 2) the role of these transporters in disease and how these transporters are affected by disease; and 3) and how selected drugs alter the function and expression of these transporters. Understanding the regulatory processes and the pathologic consequences of DAT and VMAT2 dysfunction underlies the evolution of therapeutic development for the treatment of DA-related disorders.

Fig. 1.

Presynaptic dopaminergic terminal model.

Fig. 2.

Models of DAT and VMAT2 function. (A) The movement of DA from the extracellular to cytoplasmic space through transition of DAT from an outward-facing to inward-facing state. (B) The transport of DA into synaptic vesicles from the cytoplasmic space through VMAT2, facilitated by H⁺-ATPase function.

Fig. 3.

The effects of stimulants on dopaminergic terminal function. (A–C) Exposure of dopaminergic terminals (A) to releasers (B) and reuptake inhibitors (C) alters the distribution and function of DAT and VMAT2. (B) Releasers function as DAT substrates and diffuse through the cytoplasmic membrane, leading to reversal of DA transport through the DAT. PKC-mediated DAT internalization may occur but has not been demonstrated in vivo. Releasers also reduce DA uptake into VMAT2 synaptic vesicles, by potentially functioning as a weak base to decrease vesicular pH or by binding VMAT2 directly, presumably increasing cytoplasmic DA. Finally, releasers reduce VMAT2 synaptic vesicles within the cytoplasmic fraction. (C) Reuptake inhibitors prevent DA transport via the DAT while also increasing DAT expression at the plasma membrane, increasing extracellular DA. In addition, reuptake inhibitors increase VMAT2 synaptic vesicles within the cytoplasmic fraction while reducing the number of vesicles in the membrane fraction, increasing DA content within striatal dopaminergic terminals. DAT, VMAT2, and DA are depicted as in Fig. 1. CCV, clathrin-coated vesicle; EE, early endosome; RE, recycling endosome.