title: 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.
authors: Department of Environmental Health, Rollins School of Public Health, Emory University, 1518 Clifton Road, Atlanta, GA, 30322, USA.
authors: Kelly M
authors: KM
authors: Lohr
authors: Department of Pharmacology and Toxicology, University of Toronto, ON, Canada.
authors: Shababa T
authors: ST
authors: Masoud
authors: Department of Pharmacology and Toxicology, University of Toronto, ON, Canada.
authors: Ali
authors: A
authors: Salahpour
authors: Department of Environmental Health, Rollins School of Public Health, Emory University, 1518 Clifton Road, Atlanta, GA, 30322, USA.|Center for Neurodegenerative Diseases, Emory University, Atlanta, GA, USA.|Department of Pharmacology, Emory University, Atlanta, GA, USA.|Department of Neurology, Emory University, Atlanta, GA, USA.
authors: Gary W
authors: GW
authors: Miller
mesh_terms: D000818:Animals; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000378:metabolism*; D006801:Humans; D008636:Mesencephalon / Q000378:metabolism; D017729:Presynaptic Terminals / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D004298:Dopamine
keywords: 
  DAT
  ; Parkinson's disease; VMAT2; dopamine