Rapid regulation of dopamine transporter function by substrates, blockers and presynaptic receptor ligands
Introduction
Following its release, dopamine's interaction with pre- and postsynaptic receptors is terminated primarily via high affinity uptake by plasmalemmal dopamine transporters. By removing extracellular dopamine and recycling it back into the neuron, the transporter plays a key role in shaping neurotransmission mediated by the nigrostriatal and mesocorticolimbic dopaminergic pathways. Regulation of dopamine transporter function is therefore likely to have profound effects on signaling by neurons in these pathways. An extreme example of this comes from studies in mice with a targeted gene deletion of the dopamine transporter produced by homologous recombination Gainetdinov and Caron, 2003, Giros et al., 1996. Relative to wild-type controls, dopamine transporter knockout mice have marked reductions in tyrosine hydroxylase-mediated dopamine synthesis Jaber et al., 1999, Jones et al., 1998a, presynaptic vesicular dopamine stores (Jones et al., 1998b), and stimulated dopamine release Benoit-Marand et al., 2000, Jones et al., 1998a. In addition, the protein levels and function of presynaptic dopamine D2 autoreceptors and postsynaptic dopamine D1 and D2 receptors are significantly down-regulated Giros et al., 1996, Jones et al., 1999. These appear to be compensatory changes in response to the markedly enhanced concentrations of extracellular dopamine in the null mutant mice. For example, following single-pulse stimulation of the medial forebrain bundle, extracellular dopamine in the striatum is five times higher than that measured in wild-type controls and has a 300-fold longer lifetime (Jones et al., 1998a). Consistent with enhanced dopaminergic neurotransmission, dopamine transporter knockout mice are hyperactive and exhibit cognitive and sensorimotor gating deficits Giros et al., 1996, Spielewoy et al., 2000.
Although deletion of the dopamine transporter offers a powerful tool to study the transporter's role in dopaminergic neurotransmission, more transient regulation of transporter activity is an important mechanism by which functional changes can occur in the native system. Of course, it has long been appreciated that monoamine transporter blockers like cocaine reversibly inhibit uptake activity by competing with substrate for binding to the transporter. However, recent studies have shown that transporter activity can be altered more persistently after exposure to and removal of transporter substrates and blockers, as well as presynaptic receptor ligands. Changes in transporter conformation due to posttranslational modification(s) and resulting changes in either affinity of the transporter for dopamine, Na+ or Cl−, or translocation kinetics could explain this rapid (minutes) regulation. Alternatively, changes in the number of transporters expressed at the cell surface could be the explanation. Interestingly, the bulk of the evidence supports the latter mechanism.
Thus, Na+/Cl− dependent neurotransmitter transporters, which include transporters for dopamine, norepinephrine, serotonin (5-hydroxytryptamine; 5-HT), γ-aminobutyric acid (GABA), and glycine, undergo trafficking to and from the cell membrane and these events are regulated by a variety of intrinsic cellular processes Beckman and Quick, 1998, Blakely and Bauman, 2000, Hoffman et al., 1998, Reith et al., 1997, Robinson, 2002, Torres et al., 2003b, Zahniser and Doolen, 2001. Transporter trafficking is a constitutive process Deken et al., 2003, Hicke, 1999, Loder and Melikian, 2003, allowing rapid up- and down-regulation of transporter expression at the cell surface and, thus, transport activity. For example, activation of protein kinase C pathways by phorbol esters inhibits dopamine transporter function by reducing the maximal velocity of transport (i.e., Vmax) in human dopamine transporter-expressing Xenopus laevis oocytes (Zhu et al., 1997), heterologous cells expressing the human or rat forms of the dopamine transporter Huff et al., 1997, Kitayama et al., 1994, Pristupa et al., 1998, Zhang et al., 1997 and synaptosomes prepared from rat striatum Copeland et al., 1996, Vaughan et al., 1997. The number of dopamine transporter binding sites on the surface of the oocytes, as well as cell-surface expression measured by electrophysiology, is also reduced (Zhu et al., 1997). These effects are due, at least in vitro, to enhanced transporter internalization and are blocked by protein kinase C inhibitors such as staurosporine Chang et al., 2001, Daniels and Amara, 1999, Melikian and Buckley, 1999. Transporter substrates and blockers are also capable of modifying dopamine transporter function, and in this review, we focus on the rapid, typically reversible, regulation in function that they produce. We also discuss the role of receptor-mediated regulation of transporter function, with particular emphasis on the dopamine D2 receptor. Several recent reviews discuss chronic regulation of transporters and its influence on various signaling pathways and, ultimately, on behavior Gainetdinov and Caron, 2003, Torres et al., 2003b, Zahniser and Doolen, 2001. Thus, discussion of chronic regulation will not be a focus here.
Section snippets
Model and native cell systems
The function of the dopamine transporter has been studied in vitro, using heterologous cells, primary neuronal cultures, and brain tissue preparations, and in vivo, in the intact brains of rodents and primates. The cloning of the human and rat dopamine transporters Giros et al., 1992, Kilty et al., 1991, Shimada et al., 1991 and subsequent development of model cell systems (Eshleman et al., 1995), in particular, have afforded great advances in the study of the mechanisms that underlie
Regulation of function by substrates
Substrates for the dopamine transporter, which bind to the transporter and are translocated across the membrane, can produce marked down-regulation of transporter function subsequent to their binding. The substrates that have been studied most frequently include amphetamines, dopamine and tyramine. Those with the most potent and consistent effects appear to be methamphetamine and amphetamine.
Regulation of function by blockers
Compared to substrate-induced down-regulation, the acute regulation by the transporter blocker cocaine appears to be in the opposite direction—an up-regulation of dopamine transporter activity. However, acute functional regulation by other blockers has been reported only infrequently, so generalizations about the effects of blockers should be made with care. Nevertheless, up-regulation of dopamine transporters in response to repeated cocaine administration has been described in both humans and
Regulation of function by presynaptic receptor ligands
Neurotransmitters and drugs that bind to a number of different presynaptic receptors on dopaminergic neurons have the capacity to regulate dopamine transporter function as well. Dopamine receptors and the D2 subtype in particular, have been the focus of several studies that, when taken together, suggest that activation of dopamine D2 receptors up-regulates transporter function both in vivo and in vitro. Activation of GABAB, metabotropic glutamate, nicotinic acetylcholine, 5-HT, σ2, and κ-opioid
Summary and future directions
Using model and native cell systems and measuring dopamine transporter function both in vitro and in vivo, acute exposure to transporter substrates, transporter blockers, and a variety of presynaptic receptor ligands has been shown to have the capacity to regulate rapidly dopamine transporter function (Fig. 1). At the appropriate concentrations or doses, transporter function is reduced by substrates and enhanced by the blocker cocaine-effects opposite to those produced by direct interaction of
Acknowledgments
We gratefully acknowledge support from the National Institute on Drug Abuse (DA 04216 and DA 15050).
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