The plasma membrane monoamine transporters terminate neurotransmission by removing dopamine, norepinephrine, or serotonin from the synaptic cleft between neurons. Specific inhibitors for these transporters, including the abused psychostimulants cocaine and amphetamine and the tricyclic and SSRI classes of antidepressants, exert their physiological effects by interfering with synaptic uptake and thus prolonging the actions of the monoamine. Pharmacological, biochemical, and immunological characterization of the many site-directed, chimeric, and deletion mutants generated for the plasma membrane monoamine transporters have revealed much about the commonalities and dissimilarities between transporter substrate, ion, and inhibitor binding sites. Mutations that alter the binding affinity or substrate uptake inhibition potency of inhibitors by at least 3-fold are the focus of this review. These findings are clarifying the picture regarding substrate uptake inhibitor/transporter protein interactions at the level of the drug pharmacophore and the amino acid residue, information necessary for rational design of novel medications for substance abuse and a variety of psychiatric disorders.
Cocaine, amphetamines and other psychostimulants inhibit synaptic dopamine uptake by interfering with dopamine transporter (DAT) function. The resultant potentiation of dopaminergic neurotransmission is associated with psychostimulant addiction. Fluctuations in dopamine uptake inhibition potency (DUIP) were observed for classical DAT blockers including cocaine, mazindol, methylphenidate (Ritalin™) and benztropine in CHO cells expressing wildtype DAT; cocaine potency also decreased in DAT-expressing non-neuronal COS-7 cells and neuronal N2A neuroblastoma cells. In contrast, the DAT substrate (+)-amphetamine did not display this DUIP fluctuation. In parallel experiments, no fluctuation was observed for the apparent binding affinities of these 5 drugs. The DUIP decrease appeared to correlate with an increase in cell surface DAT expression level, as measured by B max values and confocal microscopy. The fact that the DUIP profile of amphetamine diverged from that of the classical DAT blockers is consistent with the idea of fundamental differences between the mechanisms of abused psychostimulant DAT substrates and inhibitors. Identification of the cellular factors that underlie the DAT inhibitor DUIP fluctuation phenomenon may be relevant to anti-psychostimulant drug discovery efforts.
A BSTRACTThe plasma membrane monoamine transporters terminate neurotransmission by removing dopamine, norepinephrine, or serotonin from the synaptic cleft between neurons. Specifi c inhibitors for these transporters, including the abused psychostimulants cocaine and amphetamine and the tricyclic and SSRI classes of antidepressants, exert their physiological effects by interfering with synaptic uptake and thus prolonging the actions of the monoamine. Pharmacological, biochemical, and immunological characterization of the many site-directed, chimeric, and deletion mutants generated for the plasma membrane monoamine transporters have revealed much about the commonalities and dissimilarities between transporter substrate, ion, and inhibitor binding sites. Mutations that alter the binding affi nity or substrate uptake inhibition potency of inhibitors by at least 3-fold are the focus of this review. These fi ndings are clarifying the picture regarding substrate uptake inhibitor/transporter protein interactions at the level of the drug pharmacophore and the amino acid residue, information necessary for rational design of novel medications for substance abuse and a variety of psychiatric disorders.K EYWORDS: transporter , neurotransmitter , antidepressant , addiction , cocaine INTRODUCTIONPlasma membrane transporters constitute the primary mechanism for synaptic clearance of neurotransmitter following Ca 2+ -mediated exocytosis from synaptic vesicles. These proteins are responsible for translocating the cognate neurotransmitter from the extracellular space into the cytoplasm, at which point the neurotransmitter may be packaged into synaptic vesicles and recycled. The dopamine transporter (DAT), norepinephrine transporter (NET), and serotonin transporter (SERT) comprise the plasma membrane monoamine transporters, a subfamily that has been associated with psychostimulant actions and abuse, Parkinson ' s disease, attention defi cit hyperactivity disorder, schizophrenia, narcolepsy, Lesch-Nyhan disease, postural hypotension, anxiety-related disorders, autism, and depression. [1][2][3][4][5][6][7][8][9][10][11][12][13][14] The plasma membrane monoamine transporters have been and will continue to be important therapeutic targets. Structure-function studies on the DAT, NET, and SERT can only increase the precision of rational drug design in treating the conditions mentioned above.The plasma membrane monoamine transporters are members of the 12 transmembrane (TM) domain neurotransmitter:sodium symporter (NSS) family, 15 in which electrogenic transport of a neurotransmitter substrate across the cell membrane is driven by the naturally occurring neuronal Na + gradient. Cotransport of Cl -is also required for the DAT, NET and SERT; the SERT additionally transports K + , but in antiport fashion. 16 Aligning the amino acid sequences of the NSS family members guides delineation of monoamine transporter TM domain borders and other aspects of transporter secondary structure ( Figure 1 , Table 1 ). 17 Such a sequence alignment can also ...
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