Biomaterial Database

Interference of the noradrenergic neurotoxin DSP4 with neuronal and nonneuronal monoamine transporters. 2009

Birger Wenge, and Heinz Bönisch

Institute of Pharmacology and Toxicology, University of Bonn, Reuterstrasse 2 B, Bonn, Germany.

The haloalkylamine DSP4 (N[-2-chloroethyl]-N-ethyl-2-bromobenzylamine) is a noradrenergic neurotoxin, which is used for the chemical denervation of noradrenergic neurons, and it has been proposed to be a selective substrate for the neuronal, Na(+)- and Cl(-)-dependent noradrenaline transporter (NAT). In the present study, we investigated whether DSP4 not only interacts with the human NAT (hNAT) but also with other neuronal monoamine transporters such as the transporters for dopamine (hDAT) and serotonin (hSERT) or with nonneuronal (Na(+)-independent) monoamine transporters also known as organic cation transporters (OCTs), such as hOCT(1), hOCT(2), and hOCT(3). Using human embryonic kidney HEK293 cells heterologously expressing the corresponding transporter, we show that DSP4 irreversibly inhibits the hNAT, hDAT, hSERT, and hOCT(3). However, this inhibition includes a reversible component at the hDAT, hSERT, and hOCT(3) but not at the hNAT. The inhibitory potency of DSP4 at the neuronal transporters was highest at the hNAT (IC(50) about 5 microM), and it was about five and 40 times lower at the hSERT and hDAT, respectively. DSP4 inhibited all three hOCTs with high potency (IC(50) about 1 microM) but in a completely reversible manner at hOCT(1) and hOCT(2). Cytotoxicity by 24-h exposure of hNAT- or hOCT-expressing cells to low DSP4 concentrations (<10 microM) could be observed only in hNAT-expressing cells. Thus, DSP4's high-affinity uptake through the NAT together with its completely irreversible mode of interaction with the NAT may contribute to its selectivity as noradrenergic neurotoxin.

UI	MeSH Term	Description	Entries
D002460	Cell Line	Established cell cultures that have the potential to propagate indefinitely.	Cell Lines,Line, Cell,Lines, Cell
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000255	Adenosine Triphosphate	An adenine nucleotide containing three phosphate groups esterified to the sugar moiety. In addition to its crucial roles in metabolism adenosine triphosphate is a neurotransmitter.	ATP,Adenosine Triphosphate, Calcium Salt,Adenosine Triphosphate, Chromium Salt,Adenosine Triphosphate, Magnesium Salt,Adenosine Triphosphate, Manganese Salt,Adenylpyrophosphate,CaATP,CrATP,Manganese Adenosine Triphosphate,MgATP,MnATP,ATP-MgCl2,Adenosine Triphosphate, Chromium Ammonium Salt,Adenosine Triphosphate, Magnesium Chloride,Atriphos,Chromium Adenosine Triphosphate,Cr(H2O)4 ATP,Magnesium Adenosine Triphosphate,Striadyne,ATP MgCl2
D001596	Benzylamines	Toluenes in which one hydrogen of the methyl group is substituted by an amino group. Permitted are any substituents on the benzene ring or the amino group.	Phenylmethylamine,alpha-Aminotoluene,alpha Aminotoluene
D014179	Neurotransmitter Uptake Inhibitors	Drugs that inhibit the transport of neurotransmitters into axon terminals or into storage vesicles within terminals. For many transmitters, uptake determines the time course of transmitter action so inhibiting uptake prolongs the activity of the transmitter. Blocking uptake may also deplete available transmitter stores. Many clinically important drugs are uptake inhibitors although the indirect reactions of the brain rather than the acute block of uptake itself is often responsible for the therapeutic effects.	Reuptake Inhibitors, Neurotransmitter,Transmitter Uptake Inhibitors, Neuronal,Inhibitors, Neurotransmitter Uptake,Uptake Inhibitors, Neurotransmitter,Inhibitors, Neurotransmitter Reuptake,Neurotransmitter Reuptake Inhibitors
D050483	Dopamine Plasma Membrane Transport Proteins	Sodium chloride-dependent neurotransmitter symporters located primarily on the PLASMA MEMBRANE of dopaminergic neurons. They remove DOPAMINE from the EXTRACELLULAR SPACE by high affinity reuptake into PRESYNAPTIC TERMINALS and are the target of DOPAMINE UPTAKE INHIBITORS.	Dopamine Plasma Membrane Transporter Proteins,Neurotransmitter Transport Proteins, Dopamine-Specific,Neurotransmitter Transporters, Dopamine-Specific,DAT Dopamine Transporter,DAT Dopamine Transporter Proteins,Dopamine Carriers,Dopamine Transporter,Dopamine Transporter Proteins,Dopamine Uptake Complex,SLC6A3 Protein,Solute Carrier Family 6 (Neurotransmitter Transporter), Member 3 Protein,Carriers, Dopamine,Dopamine Transporter, DAT,Dopamine-Specific Neurotransmitter Transporters,Neurotransmitter Transport Proteins, Dopamine Specific,Neurotransmitter Transporters, Dopamine Specific,Protein, SLC6A3,Transporter Proteins, Dopamine,Transporter, DAT Dopamine,Transporter, Dopamine,Transporters, Dopamine-Specific Neurotransmitter
D050484	Norepinephrine Plasma Membrane Transport Proteins	Sodium chloride-dependent neurotransmitter symporters located primarily on the PLASMA MEMBRANE of noradrenergic neurons. They remove NOREPINEPHRINE from the EXTRACELLULAR SPACE by high affinity reuptake into PRESYNAPTIC TERMINALS. The norepinephrine transporter regulates signal amplitude and duration at noradrenergic synapses and is the target of ADRENERGIC UPTAKE INHIBITORS.	Neurotransmitter Transporters, Noradrenaline-Specific,Norepinephrine Plasma Membrane Transporter Proteins,Norepinephrine Plasma Membrane Transporters,NET Protein, Neuronal,Noradrenaline Plasma Membrane Transport Proteins,Noradrenaline Transporter,Norepinephrine Transporter,Norepinephrine Transporter Protein,SLC6A2 Protein,Sodium-Dependent Noradrenaline Transporter,Solute Carrier Family 6 Member 2,Neuronal NET Protein,Neurotransmitter Transporters, Noradrenaline Specific,Noradrenaline Transporter, Sodium-Dependent,Noradrenaline-Specific Neurotransmitter Transporters,Sodium Dependent Noradrenaline Transporter,Transporter Protein, Norepinephrine,Transporter, Noradrenaline,Transporter, Norepinephrine,Transporters, Noradrenaline-Specific Neurotransmitter
D050486	Serotonin Plasma Membrane Transport Proteins	Sodium chloride-dependent neurotransmitter symporters located primarily on the PLASMA MEMBRANE of serotonergic neurons. They are different than SEROTONIN RECEPTORS, which signal cellular responses to SEROTONIN. They remove SEROTONIN from the EXTRACELLULAR SPACE by high affinity reuptake into PRESYNAPTIC TERMINALS. Regulates signal amplitude and duration at serotonergic synapses and is the site of action of the SELECTIVE SEROTONIN REUPTAKE INHIBITORS.	Neurotransmitter Transport Proteins, Serotonin-Specific,Neurotransmitter Transporters, Serotonin-Specific,Serotonin Plasma Membrane Transporter Proteins,5-Hydroxytryptamine Plasma Membrane Transport Protein,5HT Transporter,Platelet Serotonin Transporter,SERT Proteins,SLC6A4 Protein,Serotonectin,Serotonin Transporter,Serotonin Transporter, Platelets,Sodium-Dependent Serotonin Transporter,Solute Carrier Family 6, Member 4 Protein,5 Hydroxytryptamine Plasma Membrane Transport Protein,Neurotransmitter Transport Proteins, Serotonin Specific,Neurotransmitter Transporters, Serotonin Specific,Platelets Serotonin Transporter,Serotonin Transporter, Platelet,Serotonin Transporter, Sodium-Dependent,Serotonin-Specific Neurotransmitter Transporters,Sodium Dependent Serotonin Transporter,Transporter, Sodium-Dependent Serotonin
D018675	Toxicity Tests	An array of tests used to determine the toxicity of a substance to living systems. These include tests on clinical drugs, foods, and environmental pollutants.	Tests, Toxicity,Test, Toxicity,Toxicity Test
D020128	Inhibitory Concentration 50	The concentration of a compound needed to reduce population growth of organisms, including eukaryotic cells, by 50% in vitro. Though often expressed to denote in vitro antibacterial activity, it is also used as a benchmark for cytotoxicity to eukaryotic cells in culture.	IC50,Concentration 50, Inhibitory