title: Interactions of cations and anions with the binding of uptake blockers to the dopamine transporter.
abstract: Uptake blockers and substrates are likely to recognise a common binding domain on the dopamine neuronal transporter (DAT). Among cations that form ionic gradients at the level of the cellular plasma membrane, Na+ is the only one that can stimulate their binding. The binding stimulation appears over Na+ concentrations ranging from 0 to 10-60 mM; at higher Na+ concentrations, binding reaches a plateau or decreases, according to the uptake blocker that is studied. The majority of the other cations, including K+, Ca2+, Mg2+ and Tris+, inhibit the binding of uptake blockers. Several metals impair binding to the DAT and/or the dopamine transport, but, under specific conditions, some of them, and chiefly Zn2+, stimulate binding. The complex relationships between cations, uptake blockers and the DAT suggest that cations recognise at least three different sites: the first one, site 1, is for cation-induced binding inhibition; the second one, site 2, is for Na+-induced binding stimulation; and the third one, site 3, is for Zn2+-induced binding stimulation. Modelling of the interactions between Na+, K+ and radioligands allows a better understanding of the effects of cations at sites 1 and 2, and of uptake blockers at site 1. Some anions also facilitate the binding of uptake blockers to the DAT, as far as they are associated with Na+. The dependence of the binding of dopamine on ions could be involved in its preferential inward transport and used by uptake blockers for their own binding to the DAT.
authors: UMR CNRS 6036, IFRMP 23, Laboratoire de Neuropsychopharmacologie expérimentale, 22 Boulevard Gambetta, 76000 Rouen, France. Jean-Jacques.Bonnet@univ-rouen.fr
authors: Jean-Jacques
authors: JJ
authors: Bonnet
mesh_terms: D000818:Animals; D000838:Anions; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D002412:Cations; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D008562:Membrane Glycoproteins; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism
chemical_list: D000838:Anions; D002412:Cations; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008562:Membrane Glycoproteins; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C493214:SLC6A3 protein, human; D012964:Sodium