Membrane transporters as mediators of synaptic dopamine dynamics: implications for disease

Abstract

Dopamine was first identified as a neurotransmitter localized to the midbrain over 50 years ago. The dopamine transporter (DAT; SLC6A3) and the vesicular monoamine transporter 2 (VMAT2; SLC18A2) are regulators of dopamine homeostasis in the presynaptic neuron. DAT transports dopamine from the extracellular space into the cytosol of the presynaptic terminal. VMAT2 then packages this cytosolic dopamine into vesicular compartments for subsequent release upon neurotransmission. Thus, DAT and VMAT2 act in concert to move the transmitter efficiently throughout the neuron. Accumulation of dopamine in the neuronal cytosol can trigger oxidative stress and neurotoxicity, suggesting that the proper compartmentalization of dopamine is critical for neuron function and risk of disease. For decades, studies have examined the effects of reduced transporter function in mice (e.g. DAT-KO, VMAT2-KO, VMAT2-deficient). However, we have only recently been able to assess the effects of elevated transporter expression using BAC transgenic methods (DAT-tg, VMAT2-HI mice). Complemented with in vitro work and neurochemical techniques to assess dopamine compartmentalization, a new focus on the importance of transporter proteins as both models of human disease and potential drug targets has emerged. Here, we review the importance of DAT and VMAT2 function in the delicate balance of neuronal dopamine.

Keywords: DAT; Parkinson's disease; VMAT2; dopamine.

Figure 1. Predicted model of dopamine compartmentalization following manipulation of DAT and VMAT2

(A) High DAT and low VMAT2 levels would theoretically result in an accumulation of cytosolic dopamine and minimal dopamine release. (B) Normal transporter levels would provide intermediate dopamine content. (C) Low DAT and high VMAT2 levels would theoretically result in low cytosolic dopamine content and elevated extracellular dopamine. (D) A summary of the interaction between DAT and VMAT2 function and resulting dopamine output. Increasing DAT function leads to greater uptake of dopamine from the extracellular space into the cytosol of the presynaptic neuron. This results in higher cytosolic and lower extracellular dopamine levels. Conversely, increasing VMAT2 function enhances packaging of cytosolic dopamine into vesicles, thus reducing cytosolic dopamine levels. Larger vesicular stores also translate into greater amounts of dopamine being released when the neuron in activated, thus increasing extracellular dopamine levels. This is a simplistic model of DAT and VMAT2 function that does not account for other contributors or adaptive changes in the dopamine system that can also influence overall dopamine levels.