title: The neurotoxins 1-methyl-4-phenylpyridinium and 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine are substrates for the organic cation transporter in renal brush border membrane vesicles.
abstract: We examined the effects of the neurotoxins 1-methyl-4-phenyl-pyridinium (MPP+) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on the transport of the prototypic organic cation, N1-[3H]methylnicotinamide ([3H]NMN), in canine renal brush border membrane vesicles. A dose-response curve for MPTP and its oxidized metabolite, MPP+, revealed IC50 values of 160 and 16 microM, respectively. MPTP (5 mM) and MPP+ (5 mM), maximally inhibited H+-driven NMN (50 microM) uptake by 86.0 and 86.6%, respectively. Additionally, serotonin (0.5 mM) and harmaline (0.5 mM) inhibited NMN transport by 65.8 and 87.1%, respectively. Mepiperphenidol (Darstine) (0.5 mM), a classical organic cation competitor, inhibited NMN transport by 80.6%. However, dopamine (0.5 mM) was not as effective and resulted in only 24.9% inhibition. The cationic specificity was demonstrated by showing that MPP+ and MPTP had no effect on the transport of the organic anion, p-aminohippurate. Additionally, the effect of MPP+ on NMN was not due to either a voltage effect or vesicle disruption. In countertransport studies, MPTP acted as an elicitor of NMN counterflow and produced trans stimulation whereas MPP+ did not and resulted in trans inhibition. Inasmuch as transport involves both binding and translocation we speculate that MPTP binds and is translocated; in contrast MPP+ binds and is not translocated. These reagents may serve as a basis for elucidating the structure-activity requirements of the organic cation/H+ antiporter.
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D015655:1-Methyl-4-phenylpyridinium; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002412:Cations / Q000378:metabolism*; D004285:Dogs; D007672:Kidney Cortex / Q000378:metabolism*; D008871:Microvilli / Q000378:metabolism; D009498:Neurotoxins; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000378:metabolism; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology*; D011726:Pyridinium Compounds / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014634:Valinomycin / Q000494:pharmacology; D010130:p-Aminohippuric Acid / Q000378:metabolism
chemical_list: D002412:Cations; D009498:Neurotoxins; D011725:Pyridines; D011726:Pyridinium Compounds; D014634:Valinomycin; D009536:Niacinamide; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D015655:1-Methyl-4-phenylpyridinium; C024058:N(1)-methylnicotinamide; D010130:p-Aminohippuric Acid