Effect of CH3HgCl and several transition metals on the dopamine neuronal carrier; peculiar behaviour of Zn2+.
CH3Hg+ and metal ions inhibited the specific binding of (1-[2-(diphenylmethoxy)ethyl]-4-(3-phenyl-2-[1-3H]propenyl) piperazine) ([3H]GBR 12783) to the dopamine neuronal carrier present in membranes from rat striatum with a general rank order of potency CH3Hg+ > Cu2+ > Cd2+ > Zn2+ > Ni2+ = Mn2+ = Co2+, suggesting that -SH groups are chiefly involved in this inhibition. Five millimolar dithiothreitol reversed the rather stable block of the specific binding produced by Cd2+ or Zn2+. An increase in the concentration of Na+, or addition of either K+ or Ca2+ reduced the inhibitory effects of metal cations, except Cu2+. Zn2+ (3 microM) reduced the inhibitory potency of Cd2+ on the binding but was ineffective against CH3Hg+ and Cu2+. Zn2+ at 0.3 to 10 microM significantly enhanced the specific binding of [3H]GBR 12783 and [3H]cocaine by 42 to 146%. Zn2+ (3 microM) increased the affinity of all pure uptake inhibitors tested and of the majority of the substrates for the [3H]GBR 12783 binding site. Dissociation experiments revealed that Zn2+ both inhibited and enhanced the [3H]GBR 12783 binding by recognizing amino acids located close to or in the radioligand binding site. Micromolar concentrations of Zn2+ noncompetitively blocked the [3H]dopamine uptake but they did not modify the block of the transport provoked by pure uptake inhibitors. These findings suggest that Na+, K+, Ca2+ and metal ions could recognize some -SH groups located in the [3H]GBR 12783 binding site; low concentrations of Zn2+ could allow a protection of these -SH groups.
Bonnet
J J
JJ
ERS 019 du CNRS, UFR de Médecine & Pharmacie de Rouen, Saint Etienne du Rouvray, France.
Benmansour
S
S
Amejdki-Chab
N
N
Costentin
J
J
D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D001692:Biological Transport / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism*; D002413:Cations, Divalent; D003042:Cocaine / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004229:Dithiothreitol / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D008670:Metals / Q000494:pharmacology; D008767:Methylmercury Compounds / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010879:Piperazines / Q000378:metabolism*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D015032:Zinc / Q000494:pharmacology*
D002352:Carrier Proteins; D002413:Cations, Divalent; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D008670:Metals; D008767:Methylmercury Compounds; D009419:Nerve Tissue Proteins; D010879:Piperazines; C039737:1-(2-(diphenylmethoxy)ethyl)-4-(3-phenyl-2-propenyl)piperazine; D003042:Cocaine; D015032:Zinc; C004925:methylmercuric chloride; D004229:Dithiothreitol; D004298:Dopamine