title: A pharmacological comparison of [3H]GBR12935 binding to rodent striatal and kidney homogenates: binding to dopamine transporters?
abstract: Binding of [3H]GBR12935 to homogenates of mouse and rat striatum and kidney was studied. [3H]GBR12935 bound to both tissue preparations with high affinity (mouse striatum Kd = 2.4 +/- 0.4 nM, n = 4; mouse kidney Kd = 3.8 +/- 0.9 nM, n = 4), in a saturable (striatal Bmax = 1.5 +/- 0.4 pmol/mg protein; kidney Bmax = 4.9 +/- 0.5 pmol/mg protein) and reversible manner. Saturation experiments revealed the presence of a single class of high affinity binding sites in both tissues of both species. Mouse kidney appeared to possess a greater density of [3H]GBR12935 binding sites than the striatum while the reverse situation prevailed for the rat. Although two dopamine uptake inhibitors, namely GBR12909 and benztropine, displaced [3H]GBR12935 binding from striatal and kidney homogenates with a similar affinity in both tissues of these species, unlabelled mazindol, (+/-)cocaine, nomifensine and amfonelic acid were significantly (P < 0.001-0.02) more potent inhibitors of [3H]GBR12935 binding in the striatum than in the kidney. While the pharmacological profile of [3H]GBR12935 binding in the rodent striatum compared well with that of the dopamine transporter reported previously, the pharmacology in the kidney was considerably different to that in the striatum. GBR12909 (1-30 mg/kg, i.p.), a close analog of GBR12935, induced significant antidiuretic and antinatriuretic effects in spontaneously hypertensive rats. These data suggest that while [3H]GBR12935 labels the dopamine uptake sites in the brain, it does not appear to label similar sites in the kidney. The mechanism of action of GBR12909 on sodium and water excretion remains to be determined.
authors.affiliation: Institute of Pharmacology, Palo Alto, CA 94304.
authors.forename: N A
authors.initials: NA
authors.lastname: Sharif
authors.forename: J L
authors.initials: JL
authors.lastname: Nunes
authors.forename: V
authors.initials: V
authors.lastname: Kalfayan
authors.forename: D L
authors.initials: DL
authors.lastname: McClelland
authors.forename: R P
authors.initials: RP
authors.lastname: Rosenkranz
authors.forename: R M
authors.initials: RM
authors.lastname: Eglen
authors.forename: R L
authors.initials: RL
authors.lastname: Whiting
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002352:Carrier Proteins / Q000378:metabolism*; D003342:Corpus Striatum / Q000378:metabolism*; D004231:Diuresis / Q000187:drug effects*; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D007668:Kidney / Q000378:metabolism*; D007700:Kinetics; D008024:Ligands; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D051379:Mice; D008813:Mice, Inbred ICR; D009318:Natriuresis / Q000187:drug effects; D009419:Nerve Tissue Proteins; D010879:Piperazines / Q000378:metabolism* / Q000494:pharmacology*; D011188:Potassium / Q000652:urine; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D014316:Tritium
chemical_list: D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008024:Ligands; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D010879:Piperazines; D014316:Tritium; C044630:1-(2 (diphenylmethoxy)ethyl)-4-(3-phenylpropyl)piperazine; D011188:Potassium; D004298:Dopamine