Molecular mechanism of citalopram and cocaine interactions with neurotransmitter transporters.
The selective serotonin reuptake inhibitors (SSRIs) and cocaine bind to the neural serotonin (5-HT) transporter (SERT) and thus inhibit presynaptic reuptake of 5-HT and elevate its concentration in the synaptic cleft. Cocaine also binds to the dopamine transporter (DAT) and to the noradrenaline transporter (NET) and inhibits presynaptic reuptake of dopamine and noradrenaline. SERT, DAT, and NET belong to the sodium/neurotransmitter symporter family, which is predicted to have a molecular structure with 12 transmembrane alpha-helices (TMHs) and intracellular amino- and carboxy terminals. We used an electron density projection map of the Escherichia coli Na+/H+ anti-porter, and site-directed mutagenesis data on DAT and SERT to construct 3-dimensional molecular models of SERT, DAT and NET. These models were used to simulate the molecular interaction mechanisms of the SSRI, S-citalopram, its less potent enantiomer, R-citalopram and of cocaine with the transporters. In the SERT model, a single amino acid (Tyr95) in TMH1 determined the transporter selectivity of S-citalopram for SERT over DAT and NET. A dipole-dipole interaction was formed between the hydroxy group of Tyr95 in SERT and the nitril group of S-citalopram, but could not be formed by S-citalopram in DAT and NET where the corresponding amino acid is a phenylalanine. The lower binding affinity of R-citalopram may be due to sterical hindrance at the binding site. The tropane ring of cocaine interacted with Tyr95 in SERT and with the corresponding phenylalanines in NET and DAT. This may explain why cocaine, but not S-citalopram, has high binding affinity to all three transporters.
Ravna
Aina Westrheim
AW
Department of Pharmacology, Institute of Medical Biology, University of Tromsø, Norway.
Sylte
Ingebrigt
I
Dahl
Svein G
SG
D000818:Animals; D001665:Binding Sites; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism*; D015283:Citalopram / Q000494:pharmacology*; D003042:Cocaine / Q000494:pharmacology*; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004347:Drug Interactions; D006801:Humans; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D017434:Protein Structure, Tertiary; D051381:Rats; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D027981:Symporters / Q000187:drug effects / Q000378:metabolism
D002352:Carrier Proteins; D015283:Citalopram; D003042:Cocaine; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D027981:Symporters; C493227:SLC6A2 protein, human; C493214:SLC6A3 protein, human; C493230:SLC6A4 protein, human; C493226:Slc6a2 protein, rat; C493216:Slc6a3 protein, rat; C493232:Slc6a4 protein, rat